5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide Derivatives Useful As a Factor XIa Inhibitors

ABSTRACT

The present invention is directed to 5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide derivatives, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing said compounds and the use of said compounds in the treatment and/or prophylaxis of thromboembolic disorders, inflammatory disorders and diseases or conditions in which plasma kallikrein activity is implicated.

FIELD OF THE INVENTION

The present invention is directed 5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide derivatives, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing said compounds, and the use of said compounds in the treatment and/or prophylaxis of thromboembolic disorders, inflammatory disorders and diseases or conditions in which plasma kallikrein activity is implicated.

BACKGROUND OF THE INVENTION

Thromboembolic diseases remain the leading cause of death in developed countries despite the availability of anticoagulants such as warfarin (COUMADIN®), heparin, low molecular weight heparins (LMWH), and synthetic pentasaccharides and antiplatelet agents such as aspirin and clopidogrel (PLAVIX®). The oral anticoagulant warfarin inhibits the post-translational maturation of coagulation factors VII, IX, X and prothrombin, and has proven effective in both venous and arterial thrombosis. However, its usage is limited due to its narrow therapeutic index with respect to bleeding safety, slow onset of therapeutic effect, numerous dietary and drug-drug interactions, and a need for monitoring and dose adjustment. Novel oral anticoagulants directly targeting either thrombin or factor Xa, e.g., dabigatran, apixaban, betrixaban, edoxaban, rivaroxaban, have been approved for both venous and arterial indications. However, the risk of bleeding is not completely eliminated, and can be as high as 2-3% per year in patients with atrial fibrillation (Quan et al., J. Med. Chem. 2018, pp 7425-7447, Vol. 61). Thus, discovering and developing safe and efficacious oral anticoagulants with minimal impacts on hemostasis for the prevention and treatment of a wide range of thromboembolic disorders has become increasingly important.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of formula (A)

wherein

R¹ is selected from the group consisting of halogen, hydroxy, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy, cyano, nitro, —NR^(A)R^(B), —C(O)—C₁₋₄alkyl, C₃₋₆cycloalkyl, phenyl and 5- to 6-membered heterocyclyl;

wherein the C₃₋₆cycloalkyl, phenyl or 5- to 6-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —NR^(A)R^(B), —(C₁₋₄alkyl)-NR^(A)R^(B), C₃₋₇cycloalkyl and 5- to 6-membered heterocyclyl;

wherein R^(A) and R^(B) are each independently selected from the group consisting of hydrogen and C₁₋₄alkyl;

a is an integer from 0 to 3;

each R² is independently selected from the group consisting of chloro, fluoro, methyl and methoxy;

R³ is selected from the group consisting of hydrogen and C₁₋₄alkyl;

R⁴ is selected from the group consisting of hydrogen, C₁₋₄alkyl and C₁₋₄alkoxy;

Q is selected from the group consisting of

(a) phenyl; wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C₂₋₄alkynyl, carboxy substituted C₂₋₄alkynyl, C₁₋₄alkoxy, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —C(O)—NR^(C)R^(D), 5- to 6-membered heteroaryl and 5- to 6-membered heterocycloalkyl;

wherein R^(C) is selected from the group consisting of hydrogen and C₁₋₄alkyl; and R^(D) is selected from the group consisting of hydrogen, hydroxy, C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, —(C₁₋₂alkylene)-O—(C₁₋₄alkyl), and cyclopropyl;

and wherein the 5- to 6-membered heteroaryl or 5- to 6-membered heterocycloalkyl is further optionally substituted with one to two substituents independently selected from the group consisting of C₁₋₂alkyl, fluorinated C₁₋₂alkyl, and oxo;

provided that no more than one substituent on the phenyl is optionally substituted 5- to 6-membered heteroaryl or 5- to 6-membered heterocycloalkyl;

(b) 9- to 10-membered nitrogen containing heterocyclyl; wherein the 9- to 10-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, —C(O)OH, —C(O)O—(C₁₋₄alkyl), C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, fluorinated C₁₋₄alkyl, —(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —O—(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —NR^(E)R^(F) and —C(O)—NR^(E)R^(F);

wherein R^(E) is selected from the group consisting of hydrogen, and C₁₋₄alkyl; and R^(F) is selected from the group consisting of hydrogen, hydroxy, and

and

wherein b is an integer from 1 to 3;

and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

The present invention is further directed to compounds of formula (I)

wherein

R¹ is selected from the group consisting of halogen, hydroxy, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy, cyano, nitro, —NR^(A)R^(B), —C(O)—C₁₋₄alkyl, C₃₋₆cycloalkyl, phenyl and 5- to 6-membered heterocyclyl;

wherein the C₃₋₆cycloalkyl, phenyl or 5- to 6-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —NR^(A)R^(B), —(C₁₋₄alkyl)-NR^(A)R^(B), C₃₋₇cycloalkyl and 5- to 6-membered heterocyclyl;

wherein R^(A) and R^(B) are each independently selected from the group consisting of hydrogen and C₁₋₄alkyl;

a is an integer from 0 to 3;

each R² is independently selected from the group consisting of chloro, fluoro, methyl and methoxy;

R³ is selected from the group consisting of hydrogen and C₁₋₄alkyl;

R⁴ is selected from the group consisting of hydrogen, C₁₋₄alkyl and C₁₋₄alkoxy;

Q is selected from the group consisting of

(a) phenyl; wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C₂₋₄alkynyl, carboxy substituted C₂₋₄alkynyl, C₁₋₄alkoxy, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —C(O)—NR^(C)R^(D), 5- to 6-membered heteroaryl and 5- to 6-membered heterocycloalkyl;

wherein R^(C) is selected from the group consisting of hydrogen and C₁₋₄alkyl; and R^(D) is selected from the group consisting of hydrogen, hydroxy, C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, —(C₁₋₂alkylene)-O—(C₁₋₄alkyl), and cyclopropyl;

and wherein the 5- to 6-membered heteroaryl or 5- to 6-membered heterocycloalkyl is further optionally substituted with one to two substituents independently selected from the group consisting of C₁₋₂alkyl, fluorinated C₁₋₂alkyl, and oxo;

provided that no more than one substituent on the phenyl is optionally substituted 5- to 6-membered heteroaryl or 5- to 6-membered heterocycloalkyl;

(b) 9- to 10-membered nitrogen containing heterocyclyl; wherein the 9- to 10-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, —C(O)OH, —C(O)O—(C₁₋₄alkyl), C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, fluorinated C₁₋₄alkyl, —(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —O—(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —NR^(E)R^(F) and —C(O)—NR^(E)R^(F);

wherein R^(E) is selected from the group consisting of hydrogen, and C₁₋₄alkyl; and R^(F) is selected from the group consisting of hydrogen, hydroxy, and

and (c)

wherein b is an integer from 1 to 3;

and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

The present invention is further directed to processes for the preparation of the compounds of formula (A) and/or compounds of formula (I). The present invention is further directed to a compound of formula (A) and/or compounds of formula (I) prepared according to any of the process(es) described herein.

Illustrative of the invention are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula (A) and/or compounds of formula (I) as described herein. An illustration of the invention is a pharmaceutical composition made by mixing a compound of formula (A) and/or compounds of formula (I) as described herein and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing a compound of formula (A) and/or compounds of formula (I) as described herein and a pharmaceutically acceptable carrier.

Exemplifying the invention are methods for the treatment and/or prophylaxis of thromboembolic disorders, inflammatory disorders or diseases or conditions in which plasma kallikrein activity is implicated, as described herein, comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

Exemplifying the invention are methods or the treatment and/or prophylaxis of thromboembolic disorders, such as arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, and venous cerebrovascular thromboembolic disorders, comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. Examples of thromboembolic disorders include, but are not limited to, unstable angina, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis.

In an embodiment, the present invention is directed to a compound of formula (A) and/or compound of formula (I) for use as a medicament. In another embodiment, the present invention is directed to a compound of formula (A) and/or compound of formula (I) for use in the treatment and/or prophylaxis of thromboembolic disorders, inflammatory disorders or diseases or conditions in which plasma kallikrein activity is implicated.

In another embodiment, the present invention is directed to a compound of formula (A) and/or compound of formula (I) for use in the treatment and/or prophylaxis of a thromboembolic disorder, such as arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, and venous cerebrovascular thromboembolic disorders. In another embodiment, the present invention is directed to a compound of formula (A) and/or compound of formula (I) for use in the treatment and/or prophylaxis of a thromboembolic disorder selected from the group consisting of unstable angina, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis. In another embodiment, the present invention is directed to a compound of formula (A) and/or compound of formula (I) for use in the treatment and/or prophylaxis of a thromboembolic disorder selected from the group consisting of hereditary angioedema (HAE) and diabetic macular edema (DME).

In another embodiment, the present invention is directed to a composition comprising a compound of formula (A) and/or compound of formula (I) for use in the treatment and/or prophylaxis of a disorder, disease or condition as described herein. In another embodiment, the present invention is directed to a composition comprising a compound of formula (A) and/or compound of formula (I) for use in the treatment and/or prophylaxis of a thromboembolic disorder, and inflammatory disorder or a disease or condition in which plasma kallikrein activity is implicated.

In another embodiment, the present invention is directed to a composition comprising a compound of formula (A) and/or compound of formula (I) for use in the treatment and/or prophylaxis of a thromboembolic disorder, such as arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, and venous cerebrovascular thromboembolic disorders. In another embodiment, the present invention is directed to a composition comprising a compound of formula (A) and/or compound of formula (I) for use in the treatment and/or prophylaxis of a thromboembolic disorder selected from the group consisting of unstable angina, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis. In another embodiment, the present invention is directed to a composition comprising a compound of formula (A) and/or compound of formula (I) for use in the treatment and/or prophylaxis of a thromboembolic disorder such as hereditary angioedema (HAE) or diabetic macular edema (DME).

Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for the treatment and/or prophylaxis of a disorder, disease or condition as described herein. Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for the treatment and/or prophylaxis of a thromboembolic disorder, an inflammatory disorder or a disease or condition in which plasma kallikrein activity is implicated.

Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for the treatment and/or prophylaxis of a thromboembolic disorder selected from the group consisting of (a) arterial cardiovascular thromboembolic disorders, (b) venous cardiovascular thromboembolic disorders, (c) arterial cerebrovascular thromboembolic disorders, and (d) venous cerebrovascular thromboembolic disorders. Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for the treatment and/or prophylaxis of (a) unstable angina, (b) an acute coronary syndrome, (c) atrial fibrillation, (d) first myocardial infarction, (e) recurrent myocardial infarction, (f) ischemic sudden death, (g) transient ischemic attack, (h) stroke, (i) atherosclerosis, (j) peripheral occlusive arterial disease, (k) venous thrombosis, (I) deep vein thrombosis, (m) thrombophlebitis, (n) arterial embolism, (o) coronary arterial thrombosis, (p) cerebral arterial thrombosis, (q) cerebral embolism, (r) kidney embolism, (s) pulmonary embolism, or (t) thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis. Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for the treatment and/or prophylaxis of: (a) hereditary angioedema (HAE) or (b) diabetic macular edema (DME).

Another example of the invention is the use of any of the compounds described herein for use in a method for treating a thromboembolic, inflammatory or a disease or condition in which plasma kallikrein activity is implicated as described herein, in a subject in need thereof.

Another example of the invention is the use of any of the compounds described herein for use in a method for the treatment and/or prophylaxis of (a) arterial cardiovascular thromboembolic disorders, (b) venous cardiovascular thromboembolic disorders, (c) arterial cerebrovascular thromboembolic disorders, or (d) venous cerebrovascular thromboembolic disorders, in a subject in need thereof. Another example of the invention is the use of any of the compounds described herein for use in a method for the treatment and/or prophylaxis of (a) unstable angina, (b) an acute coronary syndrome, (c) atrial fibrillation, (d) first myocardial infarction, (e) recurrent myocardial infarction, (f) ischemic sudden death, (g) transient ischemic attack, (h) stroke, (i) atherosclerosis, (j) peripheral occlusive arterial disease, (k) venous thrombosis, (l) deep vein thrombosis, (m) thrombophlebitis, (n) arterial embolism, (o) coronary arterial thrombosis, (p) cerebral arterial thrombosis, (q) cerebral embolism, (r) kidney embolism, (s) pulmonary embolism, or (t) thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis, in a subject in need thereof. Another example of the invention is the use of any of the compounds described herein for use in a method for the treatment and/or prophylaxis of (a) hereditary angioedema (HAE) or (b) diabetic macular edema (DME), in a subject in need thereof.

In another example, the present invention is directed to a compound as described herein, for use in a method for the treatment and/or prophylaxis of disorders, diseases or conditions as described herein, in a subject in need thereof. In another example, the present invention is directed to a compound as described herein, for use in a method for the treatment and/or prophylaxis of a thromboembolic, inflammatory disorder, or a disease or condition in which plasma kallikrein activity is implicated, as described herein, in a subject in need thereof.

In another example, the present invention is directed to a compound as described herein, for use in methods for the treatment and/or prophylaxis of thromboembolic disorder, such as arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, and venous cerebrovascular thromboembolic disorders, in a subject in need thereof. In another example, the present invention is directed to a compound as described herein, for use in methods for the treatment and/or prophylaxis of unstable angina, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis, in a subject in need thereof. In another example, the present invention is directed to a compound as described herein, for use in a method for the treatment and/or prophylaxis of hereditary angioedema (HAE) or diabetic macular edema (DME), in a subject in need thereof.

The present invention is further directed to a compound, composition (e.g. pharmaceutical composition), method of treatment, method of preparation or use, as herein described.

DETAILED DESCRIPTION OF THE INVENTION 1. 5-Oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide Derivatives

Factor XIa is a plasma serine protease involved in the regulation of blood coagulation. While blood coagulation is a necessary and important part of the regulation of an organism's homeostasis, abnormal blood coagulation can also have deleterious effects. For instance, thrombosis is the formation or presence of a blood clot inside a blood vessel or cavity of the heart. Such a blood clot can lodge in a blood vessel blocking circulation and causing a heart attack or stroke. Thromboembolic disorders are the leading cause of mortality and disability in the industrialized world.

Blood clotting is a process of control of the bloodstream essential for the survival of mammals. The process of clotting, and the subsequent dissolution of the clot after wound healing has taken place, commences after vascular injury, and can be divided into four phases. The first phase, vasoconstriction or vasocontraction, can cause a decrease in blood loss in the injured area. In the next phase, platelet activation by thrombin, platelets attach to the site of the vessel wall damage and form a platelet aggregate. In the third phase, formation of clotting complexes leads to massive formation of thrombin, which converts soluble fibrinogen to fibrin by cleavage of two small peptides. In the fourth phase, after wound healing, the thrombus is dissolved by the action of the key enzyme of the endogenous fibrinolysis system, plasmin.

Two alternative pathways can lead to the formation of a fibrin clot, the intrinsic and the extrinsic pathway. These pathways are initiated by different mechanisms, but in the later phase they converge to give a common final path of the clotting cascade. In this final path of clotting, clotting Factor X is activated. The activated Factor X is responsible for the formation of thrombin from the inactive precursor prothrombin circulating in the blood. The formation of a thrombus on the bottom of a vessel wall abnormality without a wound is the result of the intrinsic pathway. Fibrin clot formation as a response to tissue injury or an injury is the result of the extrinsic pathway. Both pathways comprise a relatively large number of proteins, which are known as clotting factors. The intrinsic pathway requires the clotting Factors V, VIII, IX, X, XI and XII and also prekallikrein, high molecular weight kininogen, calcium ions and phospholipids from platelets.

Factor XIa, a plasma serine protease involved in the regulation of blood coagulation, is initiated in vivo by the binding of tissue Factor (TF) to factor VII (FVII) to generate Factor VIIa (FVIIa). The resulting TF:FVIIa complex activates Factor IX (FIX) and Factor X (FX) that leads to the production of Factor Xa (FXa). The generated FXa catalyzes the transformation of prothrombin into small amounts of thrombin before this pathway is shut down by tissue factor pathway inhibitor (TFPI). The process of coagulation is then further propagated via the feedback activation of Factors V, VIII and XI by catalytic amounts of thrombin. (Gailani, D. et al., Arterioscler. Thromb. Vasc. Biol., 27:2507-2513 (2007)). The resulting burst of thrombin converts fibrinogen to fibrin that polymerizes to form the structural framework of a blood clot, and activates platelets, which are a key cellular component of coagulation (Hoffman, M., Blood Reviews, 17:S1-S5 (2003)). Factor XIa plays a key role in propagating this amplification loop. Epidemiological studies showed that increased circulating FXI levels in humans have been associated with increased risk for venous and arterial thrombosis, including stroke (see Quan et al. supra). In contrast, patients with congenital FXI deficiency (hemophilia C) are protected from ischemic stroke and venous thromboembolism. Therefore, Factor XIa is an attractive target for antithrombotic therapy.

In addition to stimulation via tissue factor, the coagulation system can be activated particularly on negatively charged surfaces, which include not only surface structures of foreign cells (e.g. bacteria) but also artificial surfaces such as vascular prostheses, stents and extracorporeal circulation. On the surface, initially Factor XII (FXII) is activated to Factor XIIa which subsequently activates Factor XI, attached to cell surfaces, to Factor XIa. This leads to further activation of the coagulation cascade as described above. In addition, Factor XIIa also activates bound plasma prokallikrein to plasma kallikrein (PK) which, in a potentiation loop, leads to further Factor XII activation, overall resulting in amplification of the initiation of the coagulation cascade. In addition, PK is an important bradykinin-releasing protease which leads to increased endothelial permeability. Further substrates that have been described are prorenin and prourokinase, whose activation may influence the regulatory processes of the renin-angiotensin system and fibrinolysis. The activation of PK is therefore an important link between coagulative and inflammatory processes.

The present invention is directed to compounds of formula (A)

wherein a, R¹, R², R³, R⁴, Q, etc. are as described herein; and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof. In some embodiments, the present invention is directed to compounds of formula (I)

wherein a, R¹, R², R³, R⁴, Q, etc. are as described herein; and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof. The compounds of the present invention are useful for the treatment and/or prophylaxis of thromboembolic disorders, inflammatory disorders and diseases or conditions in which plasma kallikrein activity is implicated.

In an embodiment, the present invention is directed to compounds of formula (I) wherein

R¹ is selected from the group consisting of halogen, hydroxy, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy, cyano, nitro, —NR^(A)R^(B), —C(O)—C₁₋₄alkyl, and 5- to 6-membered heterocyclyl; wherein the 5- to 6-membered heterocyclyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —NR^(A)R^(B) and —(C₁₋₂alkyl)-NR^(A)R^(B); wherein R^(A) and R^(B) are each independently selected from the group consisting of hydrogen and C₁₋₂alkyl;

a is an integer from 1 to 3;

each R² is independently selected from the group consisting of chloro, fluoro, methyl and methoxy;

R³ is selected from the group consisting of hydrogen and C₁₋₄alkyl;

R⁴ is selected from the group consisting of hydrogen, C₁₋₄alkyl and C₁₋₄alkoxy;

Q is selected from the group consisting of (a) phenyl; wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, carboxy substituted C₂₋₄alkynyl, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —C(O)—NR^(C)R^(D), 5- to 6-membered heteroaryl and 5- to 6-membered heterocycloalkyl; wherein R^(C) is selected from the group consisting of hydrogen and C₁₋₄alkyl; and R^(D) is selected from the group consisting of hydrogen, hydroxy, C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, —(C₁₋₂alkylene)-O—(C₁₋₄alkyl), and cyclopropyl; and wherein the 5- to 6-membered heteroaryl or 5- to 6-membered heterocycloalkyl is further optionally substituted with one to two substituents independently selected from the group consisting of C₁₋₄alkyl, fluorinated C₁₋₂alkyl, and oxo; provided that no more than one substituent on the phenyl is optionally substituted 5- to 6-membered heteroaryl or 5- to 6-membered heterocycloalkyl;

(b) 9- to 10-membered nitrogen containing heterocyclyl; wherein the 9- to 10-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, —C(O)OH, —C(O)O—(C₁₋₄alkyl), C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, fluorinated C₁₋₄alkyl, —(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —O—(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —NR^(E)R^(F) and —C(O)—NR^(E)R^(F); wherein R^(E) is selected from the group consisting of hydrogen, and C₁₋₄alkyl; and R^(F) is selected from the group consisting of hydrogen, hydroxy, and C₁₋₄alkyl;

and (c)

wherein b is an integer from 1 to 3;

and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

In another embodiment, the present invention is directed to compounds of formula (I) wherein

R¹ is selected from the group consisting of fluorinated C₁₋₂alkyl, triazolyl and tetrazolyl; wherein the triazolyl is optionally substituted with halogen or fluorinated C₁₋₂alkyl;

a is an integer from 1 to 2;

each R² is independently selected from chloro and fluoro;

R³ is selected from the group consisting of hydrogen and C₁₋₂alkyl;

R⁴ is selected from the group consisting of hydrogen, C₁₋₂alkyl and C₁₋₂alkoxy;

Q is selected from the group consisting of (a) phenyl; wherein the phenyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, carboxy substituted C₂₋₄alkynyl, —C(O)OH, —C(O)—NR^(C)R^(D), —C(═NH)—NH(OH), 5-membered nitrogen containing heteroaryl and 5- to 6-membered nitrogen containing heterocycloalkyl; wherein R^(C) is selected from the group consisting of hydrogen and C₁₋₂alkyl; and R^(D) is selected from the group consisting of hydrogen, hydroxy, hydroxy substituted C₁₋₄alkyl, —(C₁₋₂alkylene)-O—(C₁₋₂alkyl) and cyclopropyl; wherein the 5 membered nitrogen containing heteroaryl or and 5- to 6-membered nitrogen containing heterocycloalkyl is optionally substituted with one to two substituents independently selected from the group consisting of C₁₋₂alkyl, fluorinated C₁₋₂alkyl, oxo; provided that no more than substituent on the phenyl is optionally substituted 5-membered, nitrogen containing heteroaryl or 5- to 6-membered nitrogen containing heterocycloalkyl;

(b) 9- to 10-membered nitrogen containing heterocyclyl; wherein the 9- to 10-membered heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, —C(O)OH, C₁₋₂alkyl, hydroxy substituted C₁₋₄alkyl, fluorinated C₁₋₂alkyl, —(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —O—(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —NR^(E)R^(F) and —C(O)—NR^(E)R^(F); wherein R^(E) is selected from the group consisting of hydrogen, and C₁₋₂alkyl; and R^(F) is selected from the group consisting of hydrogen, hydroxy, C₁₋₂alkyl;

and (c)

wherein b is an integer from 1 to 3;

and stereoisomers, isotopologues, and pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to compounds of formula (I) wherein

R¹ is selected from the group consisting of difluoromethoxy, 2,2,2-trifluoroethoxy, 4-chloro-1,2,3-triazol-1-yl, 4-(trifluoromethyl)-1,2,3-triazol-1-yl, 1,2,3,4-tetrazol-1-yl and 5-deutero-1,2,3,4-tetrazol-1-yl;

a is an integer from 1 to 2;

each R² is independently selected from the group consisting of 2-fluoro, and 3-chloro;

R³ is selected from the group consisting of hydrogen and methyl;

R⁴ is selected from the group consisting of hydrogen, methyl, S*-methyl, R*-methyl, S-methoxy and R-methoxy;

Q is selected from the group consisting of (a) 2-fluoro-3-carboxy-phenyl, 3-fluoro-4-carboxy-phenyl, 3,5-difluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 4-(hydroxy-amino-carbonyl)-phenyl, 3-fluoro-4-(2-methoxy-ethyl-amino-carbonyl)-phenyl, 4-(cyclopropyl-amino-carbonyl)-phenyl, 3,5-difluoro-4-(amino-carbonyl)-phenyl, 4-(N-methyl, N-hydroxy-amino-carbonyl)-phenyl, 3-fluoro-4-(2-hydroxy-2-methyl-n-propyl-amino-carbonyl)-phenyl, 4-(N-hydroxy-amidino)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(1-methyl-imidazol-2-yl)-phenyl, 4-(2-methyl-oxazol-4-yl)-phenyl, 4-(1,2,4-oxadiazol-3-yl)-phenyl, 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl, 4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 2-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(2-methyl-1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-1-yl)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, 4-(1,2,4-triazol-3-yl)-phenyl, 4-(1-methyl-1,2,3-triazol-5-yl)-phenyl, 4-(1-methyl-1,2,4-triazol-3-yl)-phenyl, 4-(1,2,3,4-tetrazol-1-yl)-phenyl, 4-(1,2,3,4-tetrazol-5-yl)-phenyl, and 4-(1-methyl-1,2,3,4-tetrazol-5-yl)-phenyl, and 4-(pyridazin-6-yl-3(2H)-one)-phenyl;

(b) quinoxalin-6-yl, 2-(1R*-hydroxy-ethyl)-quinoxalin-6-yl, 2-(1S*-hydroxy-ethyl)-quinoxalin-6-yl, quinolin-6-yl, 4-hydroxy-quinolin-6-yl, 3-fluoro-quinolin-6-yl, 2-(ethoxy-ethoxy)-quinolin-6-yl, 2-amino-quinolin-6-yl, 2-(dimethyl-amino)-quinolin-6-yl, 4-(dimethyl-amino)-quinolin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, 3,4-dihydroquinolin-6-yl-2-one, quinazolin-7-yl-4-one, 6-methyl-quinazolin-6-yl-4-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy, N-methyl-amino-carbonyl)-indol-5-yl, 3,3-dimethyl-indolin-5-yl-2-one, indolin-5-yl-2-one, 3,3-difluoro-indolin-5-yl-2-one, 3-methyl-indolin-7-yl-2-one, 2-hydroxy-isoindolin-5-yl-1-one, 1-carboxy-2,3-dihydro-1H-inden-6-yl, 2H-indazol-5-yl, 3-hydroxy-1H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(2-methoxy-ethyl)-2H-indazol-5-yl, 1-(2-methoxy-ethyl)-1H-indazol-5-yl, 2-(difluoro-methyl)-2H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, benzimidazol-6-yl, benzoxazol-6-yl, benzothiazol-6-yl, 2-(2-hydroxy-n-prop-2-yl)-benzthiazol-5-yl, 2-(1R*-hydroxy-ethyl)-benzthiazol-5-yl, 2-(1S*-hydroxy-ethyl)-benzthiazol-5-yl, 3-amino-benzisoxazol-6-yl, 2H-benzo[d][1,2,3]triazol-5-yl, and 2-methyl-2H-benzo[d][1,2,3]triazol-5-yl, and (c) spiro[cyclopropane-1,3′-indolin-5-yl]-2′-one or spiro[cyclopentane-1,3′-indolin-5′-yl]-2-one;

and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

In another embodiment, the present invention is directed to compounds of formula (I) wherein

R¹ is selected from the group consisting of difluoro-methoxy, 2,2,2-trifluoro-ethoxy, 4-(trifluoro-methyl)-1,2,3-triazol-1-yl, and 1,2,3,4-tetrazol-1-yl

a is an integer from 1 to 2;

each R² is independently selected from the group consisting of 2-fluoro and 3-chloro;

R³ is hydrogen;

R⁴ is hydrogen;

Q is selected from the group consisting of 2-fluoro-3-carboxy-phenyl, 3-fluoro-4-carboxy-phenyl, 3,5-difluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 4-(hydroxy-amino-carbonyl)-phenyl, 3-fluoro-4-(2-methoxy-ethyl-amino-carbonyl)-phenyl, 4-(cyclopropyl-amino-carbonyl)-phenyl, 3,5-difluoro-4-(amino-carbonyl)-phenyl, 4-(N-methyl, N-hydroxy-amino-carbonyl)-phenyl, 3-fluoro-4-(2-hydroxy-2-methyl-n-propyl-amino-carbonyl)-phenyl, 4-(N-hydroxy-amidino)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(1-methyl-imidazol-2-yl)-phenyl, 4-(2-methyl-oxazol-4-yl)-phenyl, 4-(1,2,4-oxadiazol-3-yl)-phenyl, 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl, 4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 2-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(2-methyl-1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-1-yl)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, 4-(1,2,4-triazol-3-yl)-phenyl, 4-(1-methyl-1,2,3-triazol-5-yl)-phenyl, 4-(1-methyl-1,2,4-triazol-3-yl)-phenyl, 4-(1,2,3,4-tetrazol-1-yl)-phenyl, 4-(1,2,3,4-tetrazol-5-yl)-phenyl, and 4-(1-methyl-1,2,3,4-tetrazol-5-yl)-phenyl, and 4-(pyridazin-6-yl-3(2H)-one)-phenyl;

and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

In another embodiment, the present invention is directed to compounds of formula (I) wherein

R¹ is selected from the group consisting of 4-chloro-1,2,3-triazol-1-yl, 4-(trifluoro-methyl)-1,2,3-triazol-1-yl, 1,2,3,4-tetrazol-1-yl, and 5-deutero-1,2,3,4-tetrazol-1-yl;

a is 2; and the two R² are 2-fluoro and 3-chloro;

R³ is selected from the group consisting of hydrogen ad methyl

R⁴ is selected from the group consisting of hydrogen, methyl, S*-methyl, R*-methyl, S-methoxy and R-methoxy;

Q is selected from the group consisting of quinoxalin-6-yl, 2-(1R*-hydroxy-ethyl)-quinoxalin-6-yl, 2-(1S*-hydroxy-ethyl)-quinoxalin-6-yl, quinolin-6-yl, 4-hydroxy-quinolin-6-yl, 3-fluoro-quinolin-6-yl, 2-(ethoxy-ethoxy)-quinolin-6-yl, 2-amino-quinolin-6-yl, 2-(dimethyl-amino)-quinolin-6-yl, 4-(dimethyl-amino)-quinolin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, 3,4-dihydroquinolin-6-yl-2-one, quinazolin-7-yl-4-one, 6-methyl-quinazolin-6-yl-4-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy, N-methyl-amino-carbonyl)-indol-5-yl, 3,3-dimethyl-indolin-5-yl-2-one, indolin-5-yl-2-one, 3,3-difluoro-indolin-5-yl-2-one, 3-methyl-indolin-7-yl-2-one, 2-hydroxy-isoindolin-5-yl-1-one, 1-carboxy-2,3-dihydro-1H-inden-6-yl, 2H-indazol-5-yl, 3-hydroxy-1H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(2-methoxy-ethyl)-2H-indazol-5-yl, 1-(2-methoxy-ethyl)-1H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(difluoro-methyl)-2H-indazol-5-yl, benzimidazol-6-yl, benzoxazol-6-yl, benzothiazol-6-yl, 2-(2-hydroxy-n-prop-2-yl)-benzthiazol-5-yl, 2-(1R*-hydroxy-ethyl)-benzthiazol-5-yl, 2-(1S*-hydroxy-ethyl)-benzthiazol-5-yl, 3-amino-benzisoxazol-6-yl, 2H-benzo[d][1,2,3]triazol-5-yl, 2-methyl-2H-benzo[d][1,2,3]triazol-5-yl, spiro[cyclopropane-1,3′-indolin-5-yl]-2′-one or spiro[cyclopentane-1,3′-indolin-5′-yl]-2-one;

and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

In another embodiment, the present invention is directed to compounds of formula (I) wherein

R¹ is selected from the group consisting of difluoromethoxy, 2,2,2-trifluoroethoxy, 4-(trifluoromethyl)-1,2,3-triazol-1-yl, 1,2,3,4-tetrazol-1-yl and 5-deutero-1,2,3,4-tetrazol-1-yl;

a is an integer from 1 to 2;

each R² is independently selected from the group consisting of 2-fluoro, and 3-chloro;

R³ is selected from the group consisting of hydrogen and methyl;

R⁴ is selected from the group consisting of hydrogen, methyl, S*-methyl, and R-methoxy;

Q is selected from the group consisting of (a) 3-fluoro-4-carboxy-phenyl, 3,5-difluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 3-fluoro-4-(2-methoxy-ethyl-amino-carbonyl)-phenyl, 3,5-difluoro-4-(amino-carbonyl)-phenyl, 4-(N-methyl, N-hydroxy-amino-carbonyl)-phenyl, 4-(N-hydroxy-amidino)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(2-methyl-oxazol-4-yl)-phenyl, 4-(1,2,4-oxadiazol-3-yl)-phenyl, 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 2-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-1-yl)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, 4-(1,2,4-triazol-3-yl)-phenyl, 4-(1-methyl-1,2,4-triazol-3-yl)-phenyl, 4-(1,2,3,4-tetrazol-1-yl)-phenyl, and 4-(1,2,3,4-tetrazol-5-yl)-phenyl;

(b) quinoxalin-6-yl, 2-(1R*-hydroxy-ethyl)-quinoxalin-6-yl, 2-(1S*-hydroxy-ethyl)-quinoxalin-6-yl, quinolin-6-yl, 4-hydroxy-quinolin-6-yl, 3-fluoro-quinolin-6-yl, 2-amino-quinolin-6-yl, 2-(dimethyl-amino)-quinolin-6-yl, 4-(dimethyl-amino)-quinolin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, 3,4-dihydroquinolin-6-yl-2-one, quinazolin-7-yl-4-one, 6-methyl-quinazolin-6-yl-4-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy, N-methyl-amino-carbonyl)-indol-5-yl, indolin-5-yl-2-one, 3,3-difluoro-indolin-5-yl-2-one, 2H-indazol-5-yl, 3-hydroxy-1H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(2-methoxy-ethyl)-2H-indazol-5-yl, 1-(2-methoxy-ethyl)-2H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(difluoro-methyl)-2H-indazol-5-yl, benzimidazol-6-yl, benzoxazol-6-yl, benzothiazol-6-yl, 2-(1S*-hydroxy-ethyl)-benzthiazol-5-yl, 3-amino-benzisoxazol-6-yl, 2H-benzo[d][1,2,3]triazol-5-yl, and 2-methyl-2H-benzo[d][1,2,3]triazol-5-yl,

and (c) spiro[cyclopropane-1,3′-indolin-5-yl]-2′-one;

and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

In another embodiment, the present invention is directed to compounds of formula (I) wherein

R¹ is 1,2,3,4-tetrazol-1-yl;

a is 2; and the two R² are 2-fluoro, and 3-chloro;

R³ is selected from the group consisting of hydrogen and methyl;

R⁴ is selected from the group consisting of hydrogen, methyl, S*-methyl, and R-methoxy;

Q is selected from the group consisting of (a) 3-fluoro-4-carboxy-phenyl, 3,5-difluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 3-fluoro-4-(2-methoxy-ethyl-amino-carbonyl)-phenyl, 3,5-difluoro-4-(amino-carbonyl)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(1,2,4-oxadiazol-3-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 2-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-1-yl)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, 4-(1,2,4-triazol-3-yl)-phenyl, 4-(1-methyl-1,2,4-triazol-3-yl)-phenyl, and 4-(1,2,3,4-tetrazol-5-yl)-phenyl;

and (b) quinoxalin-6-yl, 2-(1R*-hydroxy-ethyl)-quinoxalin-6-yl, 2-(1S*-hydroxy-ethyl)-quinoxalin-6-yl, quinolin-6-yl, 4-hydroxy-quinolin-6-yl, 3-fluoro-quinolin-6-yl, 2-amino-quinolin-6-yl, 4-(dimethyl-amino)-quinolin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, 3,4-dihydroquinolin-6-yl-2-one, quinazolin-7-yl-4-one, 6-methyl-quinazolin-6-yl-4-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy, N-methyl-amino-carbonyl)-indol-5-yl, indolin-5-yl-2-one, 2H-indazol-5-yl, 3-hydroxy-1H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(2-methoxy-ethyl)-2H-indazol-5-yl, 2-(difluoro-methyl)-2H-indazol-5-yl, benzimidazol-6-yl, benzoxazol-6-yl, benzothiazol-6-yl 3-amino-benzisoxazol-6-yl, and 2H-benzo[d][1,2,3]triazol-5-yl;

and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

In another embodiment, the present invention is directed to compounds of formula (I) wherein

R¹ is 1,2,3,4-tetrazol-1-yl;

a is 2; and the two R² are 2-fluoro, and 3-chloro;

R³ is hydrogen;

R⁴ is selected from the group consisting of hydrogen, methyl, S*-methyl, and R-methoxy;

Q is selected from the group consisting of (a) 3-fluoro-4-carboxy-phenyl, 3,5-difluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, 4-(1,2,4-triazol-3-yl)-phenyl, 4-(1-methyl-1,2,4-triazol-3-yl)-phenyl, and 4-(1,2,3,4-tetrazol-5-yl)-phenyl;

and (b) quinoxalin-6-yl, 2-(1R*-hydroxy-ethyl)-quinoxalin-6-yl, 2-(1S*-hydroxy-ethyl)-quinoxalin-6-yl, quinolin-6-yl, 4-hydroxy-quinolin-6-yl, 2-amino-quinolin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, quinazolin-7-yl-4-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy, N-methyl-amino-carbonyl)-indol-5-yl, 2-(2-methoxy-ethyl)-2H-indazol-5-yl, 2-(difluoro-methyl)-2H-indazol-5-yl, benzothiazol-6-yl, 3-amino-benzisoxazol-6-yl, and 2H-benzo[d][1,2,3]triazol-5-yl;

and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

In another embodiment, the present invention is directed to compounds of formula (I) wherein

R¹ is 1,2,3,4-tetrazol-1-yl;

a is 2; and the two R² are 2-fluoro, and 3-chloro;

R³ is hydrogen;

R⁴ is selected from the group consisting of hydrogen, and S*-methyl;

Q is selected from the group consisting of (a) 3-fluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, and 4-(1,2,3,4-tetrazol-5-yl)-phenyl;

and (b) quinoxalin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy, N-methyl-amino-carbonyl)-indol-5-yl, and 2-(difluoro-methyl)-2H-indazol-5-yl;

and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R¹ is selected from the group consisting of halogen, hydroxy, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy, cyano, nitro, —NR^(A)R^(B), —C(O)—C₁₋₄alkyl, C₃₋₆cycloalkyl, phenyl and 5- to 6-membered heterocyclyl; wherein the C₃₋₆cycloalkyl, phenyl or 5- to 6-membered heterocyclyl is optionally substituted with one or more (preferably one to three, more preferably one to two) substituents independently selected from the group consisting of halogen, hydroxy, cyano, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —NR^(A)R^(B), and —(C₁₋₄alkyl)-NR^(A)R^(B); wherein R^(A) and R^(B) are each independently selected from the group consisting of hydrogen and C₁₋₄alkyl; and wherein the C₃₋₆cycloalkyl, phenyl or 5- to 6-membered heterocyclyl is further optionally substituted with one additional substituent selected from the group consisting of C₃₋₇cycloalkyl and 5- to 6-membered heterocyclyl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R¹ is selected from the group consisting of halogen, hydroxy, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy, cyano, nitro, —NR^(A)R^(B), —C(O)—C₁₋₄alkyl, and 5- to 6-membered heterocyclyl; wherein the 5- to 6-membered heterocyclyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —NR^(A)R^(B) and —(C₁₋₂alkyl)-NR^(A)R^(B); and wherein R^(A) and R^(B) are each independently selected from the group consisting of hydrogen and C₁₋₂alkyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R¹ is selected from the group consisting of fluorinated C₁₋₂alkyl, triazolyl and tetrazolyl; wherein the triazolyl is optionally substituted with halogen or fluorinated C₁₋₂alkyl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R¹ is selected from the group consisting of difluoromethoxy, 2,2,2-trifluoroethoxy, 4-chloro-1,2,3-triazol-1-yl, 4-(trifluoromethyl)-1,2,3-triazol-1-yl, 1,2,3,4-tetrazol-1-yl and 5-deutero-1,2,3,4-tetrazol-1-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R¹ is selected from the group consisting of difluoromethoxy, 2,2,2-trifluoroethoxy, 4-(trifluoro-methyl)-1,2,3-triazol-1-yl, and 1,2,3,4-tetrazol-1-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R¹ is selected from the group consisting of 4-chloro-1,2,3-triazol-1-yl, 4-(trifluoro-methyl)-1,2,3-triazol-1-yl, 1,2,3,4-tetrazol-1-yl, and 5-deutero-1,2,3,4-tetrazol-1-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R¹ is selected from the group consisting of difluoromethoxy, 2,2,2-trifluoroethoxy, 4-(trifluoromethyl)-1,2,3-triazol-1-yl, 1,2,3,4-tetrazol-1-yl and 5-deutero-1,2,3,4-tetrazol-1-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R¹ is 1,2,3,4-tetrazol-1-yl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein a is an integer from 0 to 2. In some embodiments, the present invention is directed to compounds of formula (I) wherein a is an integer from 1 to 2. In some embodiments, the present invention is directed to compounds of formula (I) wherein a is 1. In some embodiments, the present invention is directed to compounds of formula (I) wherein a is 2.

In some embodiments, the present invention is directed to compounds of formula (I) wherein each R² is independently selected from the group consisting of chloro, fluoro, methyl and methoxy. In some embodiments, the present invention is directed to compounds of formula (I) wherein each R² is independently selected from chloro and fluoro. In some embodiments, the present invention is directed to compounds of formula (I) wherein each R² is independently selected from the group consisting of 2-fluoro, and 3-chloro.

In some embodiments, the present invention is directed to compounds of formula (I) wherein a is 2; and the two R² are 2-fluoro and 3-chloro.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R³ is selected from the group consisting of hydrogen and C₁₋₄alkyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R³ is selected from the group consisting of hydrogen and C₁₋₂alkyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R³ is selected from the group consisting of hydrogen and methyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R³ is hydrogen.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R⁴ is selected from the group consisting of hydrogen, C₁₋₄alkyl and C₁₋₄alkoxy. In some embodiments, the present invention is directed to compounds of formula (I) wherein R⁴ is selected from the group consisting of hydrogen, C₁₋₂alkyl and C₁₋₂alkoxy. In some embodiments, the present invention is directed to compounds of formula (I) wherein R⁴ is selected from the group consisting of hydrogen, methyl, S*-methyl, R*-methyl, S-methoxy and R-methoxy. In some embodiments, the present invention is directed to compounds of formula (I) wherein R⁴ is selected from the group consisting of hydrogen, methyl, S*-methyl, and R-methoxy. In some embodiments, the present invention is directed to compounds of formula (I) wherein R⁴ is selected from the group consisting of hydrogen, and S*-methyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R⁴ is hydrogen.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is phenyl, wherein the phenyl is optionally substituted as herein described. In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is 9- to 10-membered nitrogen containing heterocyclyl, wherein the 9- to 10-membered nitrogen containing heterocyclyl is optionally substituted as herein described.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is selected from the group consisting of

(a) phenyl; wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, carboxy substituted C₂₋₄alkynyl, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —C(O)—NR^(C)R^(D), 5- to 6-membered heteroaryl and 5- to 6-membered heterocycloalkyl; wherein R^(C) is selected from the group consisting of hydrogen and C₁₋₄alkyl; and R^(D) is selected from the group consisting of hydrogen, hydroxy, C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, —(C₁₋₂alkylene)-O—(C₁₋₄alkyl), and cyclopropyl; and wherein the 5- to 6-membered heteroaryl or 5- to 6-membered heterocycloalkyl is further optionally substituted with one to two substituents independently selected from the group consisting of C₁₋₄alkyl, fluorinated C₁₋₂alkyl, and oxo; provided that no more than one substituent on the phenyl is optionally substituted 5- to 6-membered heteroaryl or 5- to 6-membered heterocycloalkyl;

(b) 9- to 10-membered nitrogen containing heterocyclyl; wherein the 9- to 10-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, —C(O)OH, —C(O)O—(C₁₋₄alkyl), C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, fluorinated C₁₋₄alkyl, —(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —O—(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —NR^(E)R^(F) and —C(O)—NR^(E)R^(F); wherein R^(E) is selected from the group consisting of hydrogen, and C₁₋₄alkyl; and R^(F) is selected from the group consisting of hydrogen, hydroxy, and C₁₋₄alkyl;

and (c)

wherein b is an integer from 1 to 3.

In some embodiments, the present invention is directed to compounds of formula (I) wherein

Q is selected from the group consisting of

(a) phenyl; wherein the phenyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, carboxy substituted C₂₋₄alkynyl, —C(O)OH, —C(O)—NR^(C)R^(D), —C(═NH)—NH(OH), 5-membered nitrogen containing heteroaryl and 5- to 6-membered nitrogen containing heterocycloalkyl; wherein R^(C) is selected from the group consisting of hydrogen and C₁₋₂alkyl; and R^(D) is selected from the group consisting of hydrogen, hydroxy, hydroxy substituted C₁₋₄alkyl, —(C₁₋₂alkylene)-O—(C₁₋₂alkyl) and cyclopropyl; wherein the 5 membered nitrogen containing heteroaryl or 5- to 6-membered nitrogen containing heterocycloalkyl is optionally substituted with one to two substituents independently selected from the group consisting of C₁₋₂alkyl, fluorinated C₁₋₂alkyl, oxo; provided that no more than substituent on the phenyl is optionally substituted 5-membered, nitrogen containing heteroaryl or 5- to 6-membered nitrogen containing heterocycloalkyl;

(b) 9- to 10-membered nitrogen containing heterocyclyl; wherein the 9- to 10-membered heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, —C(O)OH, C₁₋₂alkyl, hydroxy substituted C₁₋₄alkyl, fluorinated C₁₋₂alkyl, —(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —O—(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —NR^(E)R^(F) and —C(O)—NR^(E)R^(F); wherein R^(E) is selected from the group consisting of hydrogen, and C₁₋₂alkyl; and R^(F) is selected from the group consisting of hydrogen, hydroxy, C₁₋₂alkyl;

and (c)

wherein b is an integer from 1 to 3.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is selected from the group consisting of

(a) 2-fluoro-3-carboxy-phenyl, 3-fluoro-4-carboxy-phenyl, 3,5-difluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 4-(hydroxy-amino-carbonyl)-phenyl, 3-fluoro-4-(2-methoxy-ethyl-amino-carbonyl)-phenyl, 4-(cyclopropyl-amino-carbonyl)-phenyl, 3,5-difluoro-4-(amino-carbonyl)-phenyl, 4-(N-methyl, N-hydroxy-amino-carbonyl)-phenyl, 3-fluoro-4-(2-hydroxy-2-methyl-n-propyl-amino-carbonyl)-phenyl, 4-(N-hydroxy-amidino)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(1-methyl-imidazol-2-yl)-phenyl, 4-(2-methyl-oxazol-4-yl)-phenyl, 4-(1,2,4-oxadiazol-3-yl)-phenyl, 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl, 4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 2-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(2-methyl-1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-1-yl)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, 4-(1,2,4-triazol-3-yl)-phenyl, 4-(1-methyl-1,2,3-triazol-5-yl)-phenyl, 4-(1-methyl-1,2,4-triazol-3-yl)-phenyl, 4-(1,2,3,4-tetrazol-1-yl)-phenyl, 4-(1,2,3,4-tetrazol-5-yl)-phenyl, and 4-(1-methyl-1,2,3,4-tetrazol-5-yl)-phenyl, and 4-(pyridazin-6-yl-3(2H)-one)-phenyl;

(b) quinoxalin-6-yl, 2-(1R*-hydroxy-ethyl)-quinoxalin-6-yl, 2-(1S*-hydroxy-ethyl)-quinoxalin-6-yl, quinolin-6-yl, 4-hydroxy-quinolin-6-yl, 3-fluoro-quinolin-6-yl, 2-(ethoxy-ethoxy)-quinolin-6-yl, 2-amino-quinolin-6-yl, 2-(dimethyl-amino)-quinolin-6-yl, 4-(dimethyl-amino)-quinolin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, 3,4-dihydroquinolin-6-yl-2-one, quinazolin-7-yl-4-one, 6-methyl-quinazolin-6-yl-4-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy, N-methyl-amino-carbonyl)-indol-5-yl, 3,3-dimethyl-indolin-5-yl-2-one, indolin-5-yl-2-one, 3,3-difluoro-indolin-5-yl-2-one, 3-methyl-indolin-7-yl-2-one, 2-hydroxy-isoindolin-5-yl-1-one, 1-carboxy-2,3-dihydro-1H-inden-6-yl, 2H-indazol-5-yl, 3-hydroxy-1H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(2-methoxy-ethyl)-2H-indazol-5-yl, 1-(2-methoxy-ethyl)-1H-indazol-5-yl, 2-(difluoro-methyl)-2H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, benzimidazol-6-yl, benzoxazol-6-yl, benzothiazol-6-yl, 2-(2-hydroxy-n-prop-2-yl)-benzthiazol-5-yl, 2-(1R*-hydroxy-ethyl)-benzthiazol-5-yl, 2-(1S*-hydroxy-ethyl)-benzthiazol-5-yl, 3-amino-benzisoxazol-6-yl, 2H-benzo[d][1,2,3]triazol-5-yl, and 2-methyl-2H-benzo[d][1,2,3]triazol-5-yl,

and (c) spiro[cyclopropane-1,3′-indolin-5-yl]-2′-one or spiro[cyclopentane-1,3′-indolin-5′-yl]-2-one.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is selected from the group consisting of (a) 3-fluoro-4-carboxy-phenyl, 3,5-difluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 3-fluoro-4-(2-methoxy-ethyl-amino-carbonyl)-phenyl, 3,5-difluoro-4-(amino-carbonyl)-phenyl, 4-(N-methyl, N-hydroxy-amino-carbonyl)-phenyl, 4-(N-hydroxy-amidino)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(2-methyl-oxazol-4-yl)-phenyl, 4-(1,2,4-oxadiazol-3-yl)-phenyl, 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 2-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-1-yl)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, 4-(1,2,4-triazol-3-yl)-phenyl, 4-(1-methyl-1,2,4-triazol-3-yl)-phenyl, 4-(1,2,3,4-tetrazol-1-yl)-phenyl, and 4-(1,2,3,4-tetrazol-5-yl)-phenyl; (b) quinoxalin-6-yl, 2-(1R*-hydroxy-ethyl)-quinoxalin-6-yl, 2-(1S*-hydroxy-ethyl)-quinoxalin-6-yl, quinolin-6-yl, 4-hydroxy-quinolin-6-yl, 3-fluoro-quinolin-6-yl, 2-amino-quinolin-6-yl, 2-(dimethyl-amino)-quinolin-6-yl, 4-(dimethyl-amino)-quinolin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, 3,4-dihydroquinolin-6-yl-2-one, quinazolin-7-yl-4-one, 6-methyl-quinazolin-6-yl-4-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy, N-methyl-amino-carbonyl)-indol-5-yl, indolin-5-yl-2-one, 3,3-difluoro-indolin-5-yl-2-one, 2H-indazol-5-yl, 3-hydroxy-1H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(2-methoxy-ethyl)-2H-indazol-5-yl, 1-(2-methoxy-ethyl)-2H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(difluoro-methyl)-2H-indazol-5-yl, benzimidazol-6-yl, benzoxazol-6-yl, benzothiazol-6-yl, 2-(1S*-hydroxy-ethyl)-benzthiazol-5-yl, 3-amino-benzisoxazol-6-yl, 2H-benzo[d][1,2,3]triazol-5-yl, and 2-methyl-2H-benzo[d][1,2,3]triazol-5-yl; and (c) spiro[cyclopropane-1,3′-indolin-5-yl]-2′-one.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is selected from the group consisting of (a) 3-fluoro-4-carboxy-phenyl, 3,5-difluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 3-fluoro-4-(2-methoxy-ethyl-amino-carbonyl)-phenyl, 3,5-difluoro-4-(amino-carbonyl)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(1,2,4-oxadiazol-3-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 2-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-1-yl)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, 4-(1,2,4-triazol-3-yl)-phenyl, 4-(1-methyl-1,2,4-triazol-3-yl)-phenyl, and 4-(1,2,3,4-tetrazol-5-yl)-phenyl; and (b) quinoxalin-6-yl, 2-(1R*-hydroxy-ethyl)-quinoxalin-6-yl, 2-(1S*-hydroxy-ethyl)-quinoxalin-6-yl, quinolin-6-yl, 4-hydroxy-quinolin-6-yl, 3-fluoro-quinolin-6-yl, 2-amino-quinolin-6-yl, 4-(dimethyl-amino)-quinolin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, 3,4-dihydroquinolin-6-yl-2-one, quinazolin-7-yl-4-one, 6-methyl-quinazolin-6-yl-4-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy, N-methyl-amino-carbonyl)-indol-5-yl, indolin-5-yl-2-one, 2H-indazol-5-yl, 3-hydroxy-1H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(2-methoxy-ethyl)-2H-indazol-5-yl, 2-(difluoro-methyl)-2H-indazol-5-yl, benzimidazol-6-yl, benzoxazol-6-yl, benzothiazol-6-yl 3-amino-benzisoxazol-6-yl, and 2H-benzo[d][1,2,3]triazol-5-yl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is selected from the group consisting of (a) 3-fluoro-4-carboxy-phenyl, 3,5-difluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, 4-(1,2,4-triazol-3-yl)-phenyl, 4-(1-methyl-1,2,4-triazol-3-yl)-phenyl, and 4-(1,2,3,4-tetrazol-5-yl)-phenyl; and (b) quinoxalin-6-yl, 2-(1R*-hydroxy-ethyl)-quinoxalin-6-yl, 2-(1S*-hydroxy-ethyl)-quinoxalin-6-yl, quinolin-6-yl, 4-hydroxy-quinolin-6-yl, 2-amino-quinolin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, quinazolin-7-yl-4-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy, N-methyl-amino-carbonyl)-indol-5-yl, 2-(2-methoxy-ethyl)-2H-indazol-5-yl, 2-(difluoro-methyl)-2H-indazol-5-yl, benzothiazol-6-yl, 3-amino-benzisoxazol-6-yl, and 2H-benzo[d][1,2,3]triazol-5-yl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is selected from the group consisting of (a) 3-fluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, and 4-(1,2,3,4-tetrazol-5-yl)-phenyl; and (b) quinoxalin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy, N-methyl-amino-carbonyl)-indol-5-yl, and 2-(difluoro-methyl)-2H-indazol-5-yl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is selected from the group consisting of 2-fluoro-3-carboxy-phenyl, 3-fluoro-4-carboxy-phenyl, 3,5-difluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 4-(hydroxy-amino-carbonyl)-phenyl, 3-fluoro-4-(2-methoxy-ethyl-amino-carbonyl)-phenyl, 4-(cyclopropyl-amino-carbonyl)-phenyl, 3,5-difluoro-4-(amino-carbonyl)-phenyl, 4-(N-methyl, N-hydroxy-amino-carbonyl)-phenyl, 3-fluoro-4-(2-hydroxy-2-methyl-n-propyl-amino-carbonyl)-phenyl, 4-(N-hydroxy-amidino)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(1-methyl-imidazol-2-yl)-phenyl, 4-(2-methyl-oxazol-4-yl)-phenyl, 4-(1,2,4-oxadiazol-3-yl)-phenyl, 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl, 4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 2-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(2-methyl-1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-1-yl)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, 4-(1,2,4-triazol-3-yl)-phenyl, 4-(1-methyl-1,2,3-triazol-5-yl)-phenyl, 4-(1-methyl-1,2,4-triazol-3-yl)-phenyl, 4-(1,2,3,4-tetrazol-1-yl)-phenyl, 4-(1,2,3,4-tetrazol-5-yl)-phenyl, and 4-(1-methyl-1,2,3,4-tetrazol-5-yl)-phenyl, and 4-(pyridazin-6-yl-3(2H)-one)-phenyl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is selected from the group consisting of (a) 3-fluoro-4-carboxy-phenyl, 3,5-difluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 3-fluoro-4-(2-methoxy-ethyl-amino-carbonyl)-phenyl, 3,5-difluoro-4-(amino-carbonyl)-phenyl, 4-(N-methyl, N-hydroxy-amino-carbonyl)-phenyl, 4-(N-hydroxy-amidino)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(2-methyl-oxazol-4-yl)-phenyl, 4-(1,2,4-oxadiazol-3-yl)-phenyl, 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 2-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-1-yl)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, 4-(1,2,4-triazol-3-yl)-phenyl, 4-(1-methyl-1,2,4-triazol-3-yl)-phenyl, 4-(1,2,3,4-tetrazol-1-yl)-phenyl, and 4-(1,2,3,4-tetrazol-5-yl)-phenyl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is selected from the group consisting of (a) 3-fluoro-4-carboxy-phenyl, 3,5-difluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 3-fluoro-4-(2-methoxy-ethyl-amino-carbonyl)-phenyl, 3,5-difluoro-4-(amino-carbonyl)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(1,2,4-oxadiazol-3-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 2-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-1-yl)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, 4-(1,2,4-triazol-3-yl)-phenyl, 4-(1-methyl-1,2,4-triazol-3-yl)-phenyl, and 4-(1,2,3,4-tetrazol-5-yl)-phenyl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is selected from the group consisting of (a) 3-fluoro-4-carboxy-phenyl, 3,5-difluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, 4-(1,2,4-triazol-3-yl)-phenyl, 4-(1-methyl-1,2,4-triazol-3-yl)-phenyl, and 4-(1,2,3,4-tetrazol-5-yl)-phenyl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is selected from the group consisting of (a) 3-fluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, and 4-(1,2,3,4-tetrazol-5-yl)-phenyl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is selected from the group consisting of quinoxalin-6-yl, 2-(1R*-hydroxy-ethyl)-quinoxalin-6-yl, 2-(1S*-hydroxy-ethyl)-quinoxalin-6-yl, quinolin-6-yl, 4-hydroxy-quinolin-6-yl, 3-fluoro-quinolin-6-yl, 2-(ethoxy-ethoxy)-quinolin-6-yl, 2-amino-quinolin-6-yl, 2-(dimethyl-amino)-quinolin-6-yl, 4-(dimethyl-amino)-quinolin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, 3,4-dihydroquinolin-6-yl-2-one, quinazolin-7-yl-4-one, 6-methyl-quinazolin-6-yl-4-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy, N-methyl-amino-carbonyl)-indol-5-yl, 3,3-dimethyl-indolin-5-yl-2-one, indolin-5-yl-2-one, 3,3-difluoro-indolin-5-yl-2-one, 3-methyl-indolin-7-yl-2-one, 2-hydroxy-isoindolin-5-yl-1-one, 1-carboxy-2,3-dihydro-1H-inden-6-yl, 2H-indazol-5-yl, 3-hydroxy-1H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(2-methoxy-ethyl)-2H-indazol-5-yl, 1-(2-methoxy-ethyl)-1H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(difluoro-methyl)-2H-indazol-5-yl, benzimidazol-6-yl, benzoxazol-6-yl, benzothiazol-6-yl, 2-(2-hydroxy-n-prop-2-yl)-benzthiazol-5-yl, 2-(1R*-hydroxy-ethyl)-benzthiazol-5-yl, 2-(1S*-hydroxy-ethyl)-benzthiazol-5-yl, 3-amino-benzisoxazol-6-yl, 2H-benzo[d][1,2,3]triazol-5-yl, 2-methyl-2H-benzo[d][1,2,3]triazol-5-yl, spiro[cyclopropane-1,3′-indolin-5-yl]-2′-one or spiro[cyclopentane-1,3′-indolin-5′-yl]-2-one.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is selected from the group consisting of (b) quinoxalin-6-yl, 2-(1R*-hydroxy-ethyl)-quinoxalin-6-yl, 2-(1S*-hydroxy-ethyl)-quinoxalin-6-yl, quinolin-6-yl, 4-hydroxy-quinolin-6-yl, 3-fluoro-quinolin-6-yl, 2-amino-quinolin-6-yl, 2-(dimethyl-amino)-quinolin-6-yl, 4-(dimethyl-amino)-quinolin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, 3,4-dihydroquinolin-6-yl-2-one, quinazolin-7-yl-4-one, 6-methyl-quinazolin-6-yl-4-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy, N-methyl-amino-carbonyl)-indol-5-yl, indolin-5-yl-2-one, 3,3-difluoro-indolin-5-yl-2-one, 2H-indazol-5-yl, 3-hydroxy-1H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(2-methoxy-ethyl)-2H-indazol-5-yl, 1-(2-methoxy-ethyl)-2H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(difluoro-methyl)-2H-indazol-5-yl, benzimidazol-6-yl, benzoxazol-6-yl, benzothiazol-6-yl, 2-(1S*-hydroxy-ethyl)-benzthiazol-5-yl, 3-amino-benzisoxazol-6-yl, 2H-benzo[d][1,2,3]triazol-5-yl, and 2-methyl-2H-benzo[d][1,2,3]triazol-5-yl; and (c) spiro[cyclopropane-1,3′-indolin-5-yl]-2′-one.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is selected from the group consisting of (b) quinoxalin-6-yl, 2-(1R*-hydroxy-ethyl)-quinoxalin-6-yl, 2-(1S*-hydroxy-ethyl)-quinoxalin-6-yl, quinolin-6-yl, 4-hydroxy-quinolin-6-yl, 3-fluoro-quinolin-6-yl, 2-amino-quinolin-6-yl, 4-(dimethyl-amino)-quinolin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, 3,4-dihydroquinolin-6-yl-2-one, quinazolin-7-yl-4-one, 6-methyl-quinazolin-6-yl-4-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy, N-methyl-amino-carbonyl)-indol-5-yl, indolin-5-yl-2-one, 2H-indazol-5-yl, 3-hydroxy-1H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(2-methoxy-ethyl)-2H-indazol-5-yl, 2-(difluoro-methyl)-2H-indazol-5-yl, benzimidazol-6-yl, benzoxazol-6-yl, benzothiazol-6-yl 3-amino-benzisoxazol-6-yl, and 2H-benzo[d][1,2,3]triazol-5-yl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is selected from the group consisting of (b) quinoxalin-6-yl, 2-(1R*-hydroxy-ethyl)-quinoxalin-6-yl, 2-(1S*-hydroxy-ethyl)-quinoxalin-6-yl, quinolin-6-yl, 4-hydroxy-quinolin-6-yl, 2-amino-quinolin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, quinazolin-7-yl-4-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy, N-methyl-amino-carbonyl)-indol-5-yl, 2-(2-methoxy-ethyl)-2H-indazol-5-yl, 2-(difluoro-methyl)-2H-indazol-5-yl, benzothiazol-6-yl, 3-amino-benzisoxazol-6-yl, and 2H-benzo[d][1,2,3]triazol-5-yl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is selected from the group consisting of (b) quinoxalin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy, N-methyl-amino-carbonyl)-indol-5-yl, and 2-(difluoro-methyl)-2H-indazol-5-yl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is

wherein b is an integer from 1 to 3.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is

wherein b is an integer from 1 to 2.

In some embodiments, the present invention is directed to compounds of formula (I) wherein Q is

wherein b is 1.

In some embodiments, the present invention is directed to one or more compounds selected from the group consisting of

-   (3S*,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-N-(2′-oxospiro[cyclopentane-1,3′-indolin]-5′-yl)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide; -   (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-N-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide; -   (3S,8aS*)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide; -   (3S,8aR*)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-N-[3-fluoro-4-(5-oxo-2H-1,2,4-oxadiazol-3-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide; -   (3S,8aS*)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(3-fluoro-4-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide; -   (3S,8R*)-4-[[7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carbonyl]amino]-2-fluoro-benzoic     acid; -   (3S,8aR*)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-N-[4-(5-oxo-2H-1,2,4-oxadiazol-3-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide; -   (3S,8aR*)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-N-[4-(1H-tetrazol-5-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide; -   (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-N-[4-(1H-triazol-5-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide; -   5-[[(3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carbonyl]amino]-3-fluoro-1H-indole-2-carboxylic     acid;

and pharmaceutically acceptable salts thereof.

One skilled in the art will recognize that, depending on substituent groups, the compounds of the present invention may contain two or more stereocenters, two of which are denoted by the “*” symbols in the structure of formula (A) as shown below

For clarity, the “*” denoted stereo-center at the indolizine carbon atom bound to R³ and R⁴ will be referred to herein as the “R³/R⁴” stereo-center; the “*” denoted stereo-center at the bridge carbon atom of the indolizine core structure will be referred to herein as the “Ring” stereo-center; and the denoted stereo-center at the indolizine carbon atom bound to the —C(O)—NH-Q group, herein referred to as the “Amide” stereo-center. One skilled in the art will recognize that in the compounds of formula (I) of the present invention, the Amide stereo-center (at the indolizine carbon atom bound to the —C(O)—NH-Q group) is present in a stereo-isomeric excess of the corresponding S-configuration.

In some embodiments, the present invention is directed to compounds of formula (A) and/or compounds of formula (I) wherein the R³/R⁴ stereocenter is present as a racemic mixture (independent of the stereo-configuration at any other stereocenter(s)). In some embodiments, the present invention is directed to compounds of formula (A) and/or compounds of formula (I) and/or compounds of formula (I) wherein the R³/R⁴ stereocenter is present in a stereoisomeric excess of the S-configuration (independent of the stereo-configuration at any other stereocenter(s)). In some embodiments, the present invention is directed to compounds of formula (A) and/or compounds of formula (I) wherein the R³/R⁴ stereocenter is present in a stereoisomeric excess of the R-configuration (independent of the stereo-configuration at any other stereocenter(s)).

In some embodiments, the present invention is directed to compounds of formula (A) and/or compounds of formula (I) wherein the R³/R⁴ stereocenter is present in a stereoisomeric excess of one of the corresponding R- or S-stereoisomers (independent of the stereo-configuration at any other stereo-center(s)).

In some embodiments of the present invention, the R³/R⁴ stereocenter is present in a stereoisomeric excess of one of the corresponding R- or S-enantiomers (independent of the stereo-configuration at any other stereo-center(s)) of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99%. Preferably, the R³/R⁴ stereocenter is present in a stereoisomeric excess of one of the corresponding R- or S-stereoisomers (independent of the stereo-configuration at any other stereo-center(s)) of greater than or equal to about 80%, preferably greater than or equal to about 90%, more preferably greater than or equal to about 93%, more preferably greater than or equal to about 95%, more preferably greater than or equal to about 97%, more preferably greater than or equal to about 98%, more preferably greater than or equal to about 99%.

In some embodiments, the present invention is directed to compounds of formula (A) and/or compounds of formula (I) wherein the Ring stereocenter is present as a racemic mixture (independent of the stereo-configuration at any other stereocenter(s)). In some embodiments, the present invention is directed to compounds of formula (A) and/or compounds of formula (I) wherein the Ring stereocenter is present in a stereoisomeric excess of the S-configuration (independent of the stereo-configuration at any other stereocenter(s)). In some embodiments, the present invention is directed to compounds of formula (A) and/or compounds of formula (I) wherein the Ring stereocenter is present in a stereoisomeric excess of the R-configuration (independent of the stereo-configuration at any other stereocenter(s)).

In some embodiments, the present invention is directed to compounds of formula (A) and/or compounds of formula (I) wherein the Ring stereocenter is present in a stereoisomeric excess of one of the corresponding R- or S-stereoisomers (independent of the stereo-configuration at any other stereo-center(s)). In some embodiments of the present invention, the Ring stereocenter is present in a stereoisomeric excess of one of the corresponding R- or S-enantiomers (independent of the stereo-configuration at any other stereo-center(s)) of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99%. Preferably, the Ring stereocenter is present in a stereoisomeric excess of one of the corresponding R- or S-stereoisomers (independent of the stereo-configuration at any other stereo-center(s)) of greater than or equal to about 80%, preferably greater than or equal to about 90%, more preferably greater than or equal to about 93%, more preferably greater than or equal to about 95%, more preferably greater than or equal to about 97%, more preferably greater than or equal to about 98%, more preferably greater than or equal to about 99%.

In some embodiments, the present invention is directed to compounds of formula (A) and/or compounds of formula (I) wherein the Ring stereocenter and the R³/R⁴ stereocenter are each present as a racemic mixture. In some embodiments, the present invention is directed to compounds of formula (A) and/or compounds of formula (I) wherein the Ring stereocenter is present in a stereoisomeric excess of its corresponding S-configuration and the R³/R⁴ stereocenter is present in a stereoisomeric excess of its corresponding S-configuration. In some embodiments, the present invention is directed to compounds of formula (A) and/or compounds of formula (I) wherein the Ring stereocenter is present in a stereoisomeric excess of its corresponding S-configuration and the R³/R⁴ stereocenter is present in a stereoisomeric excess of its corresponding R-configuration. In some embodiments, the present invention is directed to compounds of formula (A) and/or compounds of formula (I) wherein the Ring stereocenter is present in a stereoisomeric excess of its corresponding R-configuration and the R³/R⁴ stereocenter is present in a stereoisomeric excess of its corresponding S-configuration. In some embodiments, the present invention is directed to compounds of formula (A) and/or compounds of formula (I) wherein the Ring stereocenter is present in a stereoisomeric excess of its corresponding R-configuration and the R³/R⁴ stereocenter is present in a stereoisomeric excess of its corresponding R-configuration.

In some embodiments, the Amide stereo-center is present in a stereoisomeric excess of the S-stereoisomer (independent of the stereo-configuration at any other stereo-center(s)) of greater than 50%. In some embodiments, the Amide stereo-center is present in a stereoisomeric excess of the S-stereoisomer (independent of the stereo-configuration at any other stereo-center(s)) of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99%. Preferably, the Amide stereocenter is present in a stereoisomeric excess of the S-stereoisomers (independent of the stereo-configuration at any other stereo-center(s)) of greater than or equal to about 80%, preferably greater than or equal to about 90%, more preferably greater than or equal to about 93%, more preferably greater than or equal to about 95%, more preferably greater than or equal to about 97%, more preferably greater than or equal to about 98%, more preferably greater than or equal to about 99%.

Additional embodiments of the present invention include those wherein the substituents selected for one or more of the variables defined herein (i.e. a, R¹, R², R³, R⁴, Q, etc.) are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein. Additional embodiments of the present invention include those wherein the substituents selected for one or more of the variables defined herein (a, R¹, R², R³, R⁴, Q, etc.) are independently selected to correspond to any of the embodiments as defined herein.

In some embodiments, the present invention is directed to any single compound or subset of compounds independently selected from the list of representative compounds in Tables 1 and 2, below.

Representative compounds of the present invention are as listed in Tables 1 and 2, below. Unless otherwise noted, the position of R² group(s) as listed in the Tables below use the following numbering scheme:

such that the R¹ substituent is bound at the 6-position and the R² substituents are bound at the 2-, 3-, 4- and/or 5-positions of the phenyl group.

The column headed “Ring Stereo” lists the stereo-orientation at the indolizine bridge position carbon atom, denoted by “*” symbol. Compounds prepared as racemic mixtures are denoted as “RAC”. The S* and R* designations indicate that although the compound was prepared in an excess of one of the corresponding stereoisomers, the exact stereo-configuration was not determined. The S and R designations indicate that the compound was prepared in an excess of the corresponding S or R stereoisomer, with the exact stereo-configuration as noted.

The column headed “R³, R⁴¹” lists the R³ and R⁴ substituents, along with the stereo-orientation at R³/R⁴ stereocenter, as denoted by the “*” symbol. Compounds prepared as racemates list no stereo-orientation in the “R³, R⁴” column. The S*- and R*-designations in the name of either of the R³ or substituent group indicates that although the compound was prepared in an enantiomeric excess of one of the stereoisomers at the R³/R⁴ stereocenter, the exact stereo-configuration of the stereocenter was not determined. The designations S- and R- in the name of either of the R³ or R⁴ substituent group indicates that the compound was prepared in an enantiomeric excess of the corresponding S- or R-stereo-configuration at the R³/R⁴ stereocenter. In Tables 1 and 2 below, compounds indicated as (S*) at the Amide stereo-center were not specifically determined to be in the (S) configuration, but based assigned S* designation to indicate that they were prepared in an enantiomeric excess of one stereo-configuration at the Amide stereo-center.

TABLE 1 Representative Compounds of the Present Invention

Ring Example Stereo R¹ (R²)_(a) Q 5 R* 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 3-fluoro-4-(2-methoxy- chloro ethyl-amino-carbonyl)- phenyl 17 R 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(1,2,4-oxadiazol-3-yl- chloro 5-one)-phenyl 20 R 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(2-methyl-oxazol-4- chloro yl)-phenyl 24 R 4-(trifluoro-methyl)- 2-fluoro, 3- 3-fluoro-4-(amino- 1,2,3-triazol-1-yl chloro carbonyl)-phenyl 25 R 4-(trifluoro-methyl)- 3-chloro 3-fluoro-4-(amino- 1,2,3-triazol-1-yl carbonyl)-phenyl 32 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(2-carboxy-ethen-1- chloro yl)-phenyl 33 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 3,5-difluoro-4-(amino- chloro carbonyl)-phenyl 34 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(N-methyl, N- chloro hydroxy-amino- carbonyl)-phenyl 35 R* 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 3-fluoro-4-(1,2,4- chloro oxadiazol-3-yl-5-one)- phenyl 36 S* 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 3-fluoro-4-(1,2,4- chloro oxadiazol-3-yl-5-one)- phenyl 37 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 3,5-difluoro-4-carboxy- chloro phenyl 38 RAC difluoro-methoxy 2-fluoro, 3- 4-(1,2,4-oxadiazol-3-yl- chloro 5-one)-phenyl 39 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 3-fluoro-4-(amino- chloro carbonyl)-phenyl 40 RAC 2,2,2-trifluoro- 2-fluoro, 3- 4-(1,2,4-oxadiazol-3-yl- ethoxy chloro 5-one)-phenyl 41 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(amino-carbonyl)- chloro phenyl 42 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 3-fluoro-4-(1,2,4- chloro oxadiazol-3-yl-5-one)- phenyl 47 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 2-fluoro-4-(1,2,4- chloro oxadiazol-3-yl-5-one)- phenyl 48 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(1,2,3-triazol-1-yl)- chloro phenyl 49 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(1,2,3-triazol-1-yl)- chloro phenyl 50 R* 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(5-methyl-1,2,4- chloro oxadiazol-3-yl)-phenyl 51 S* 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 3-fluoro-4-carboxy- chloro phenyl 52 R* 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 3-fluoro-4-carboxy- chloro phenyl 58 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 3-fluoro-4-carboxy- chloro phenyl 63 R* 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(1,2,4-oxadiazol-3-yl- chloro 5-one)-phenyl 65 S* 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(1,2,3,4-tetrazol-5- chloro yl)-phenyl 66 R* 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(1,2,3,4-tetrazol-5- chloro yl)-phenyl 67 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(2-methyl-1,2,4- chloro oxadiazol-3-yl-5-one)- phenyl 68 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(1,2,3-triazol-5-yl)- chloro phenyl 69 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(1,2,4-triazol-3-yl)- chloro phenyl 70 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(1-methyl-1,2,3,4- chloro tetrazol-5-yl)-phenyl 71 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(1-methyl-1,2,3- chloro triazol-5-yl)-phenyl 72 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(1,2,3,4-tetrazol-5- chloro yl)-phenyl 73 RAC 1 2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(1,2,3,4-tetrazol-1- chloro yl)-phenyl 74 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(imidazol-2-yl)- chloro phenyl 75 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(1,3,4-oxadiazol-5-yl- chloro 2-one)-phenyl 76 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(1,2,4-oxadiazol-3-yl- chloro 5-one)-phenyl 77 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(1-methyl-1,2,4- chloro triazol-3-yl)-phenyl 78 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(1-methyl-imidazol-2- chloro yl)-phenyl 94 S* 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 3-fluoro-4-(2-methoxy- chloro ethyl-amino-carbonyl)- phenyl 95 R* 4-(trifluoro-methyl)- 2-fluoro, 3- 3-fluoro-4-(2-hydroxy- 1,2,3-triazol-1-yl chloro 2-methyl-n-propyl- amino-carbonyl)- phenyl 97 R 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(5-(difluoromethyl)- chloro 1,2,4-oxadiazol-3-yl)- phenyl 98 R 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(1,2,4-oxadiazol-3- chloro yl)-phenyl 99 R 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(N-hydroxy-amidino)- chloro phenyl 100 R 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(cyclopropyl-amino- chloro carbonyl)-phenyl 103 R 4-(trifluoro-methyl)- 2-fluoro, 3- 2-fluoro-3-carboxy- 1,2,3-triazol-1-yl chloro phenyl 108 S 4-(trifluoro-methyl)- 2-fluoro, 3- 3-fluoro-4-(amino- 1,2,3-triazol-1-yl chloro carbonyl)-phenyl 109 S 4-(trifluoro-methyl)- 3-chloro 3-fluoro-4-(amino- 1,2,3-triazol-1-yl carbonyl)-phenyl 111 RAC 1,2,3,4-tetrazol-1-yl 2-fluoro, 3- 4-(hydroxy-amino- chloro carbonyl)-phenyl

93 RAC 4-(trifluoro-methyl)- 2-fluoro, 3- 4-(pyridazin-6-yl-3(2H)- 1,2,3-triazol-1-yl chloro one)-phenyl

TABLE 2 Representative Compounds of the Present Invention

Ring ID No. Stereo R¹ (R²)_(a) R³, R⁴ Q 6 R 1,2,3,4- 2-fluoro, 3- H, H 2-amino-quinolin-6-yl tetrazol-1-yl chloro 7 R 1,2,3,4- 2-fluoro, 3- H, H 3,3-dimethyl-indolin- tetrazol-1-yl chloro 5-yl-2-one 8 R 1,2,3,4- 2-fluoro, 3- H, H spiro[cyclopentane- tetrazol-1-yl chloro 1,3′-indolin-5′-yl]-2′- one 9 R 1,2,3,4- 2-fluoro, 3- H, H 4-hydroxy-quinolin-6- tetrazol-1-yl chloro yl 10 R 1,2,3,4- 2-fluoro, 3- H, H 3-fluoro-quinolin-6-yl tetrazol-1-yl chloro 11 R 1,2,3,4- 2-fluoro, 3- H, H 2-(dimethyl-amino)- tetrazol-1-yl chloro quinolin-6-yl 12 R 1,2,3,4- 2-fluoro, 3- H, H indolin-5-yl-2-one tetrazol-1-yl chloro 13 R 1,2,3,4- 2-fluoro, 3- H, H 3,4-dihydroquinolin- tetrazol-1-yl chloro 6-yl-2-one 14 R 1,2,3,4- 2-fluoro, 3- H, H 6-methyl-quinazolin- tetrazol-1-yl chloro 6-yl-4-one 15 R 1,2,3,4- 2-fluoro, 3- H, H 3,3-difluoro-indolin-5- tetrazol-1-yl chloro yl-2-one 16 R 1,2,3,4- 2-fluoro, 3- H, H 2-methyl-2H- tetrazol-1-yl chloro benzo[d][1,2,3]triazol- 5-yl 18 R 1,2,3,4- 2-fluoro, 3- H, H quinazolin-7-yl-4-one tetrazol-1-yl chloro 19 R 1,2,3,4- 2-fluoro, 3- H, H 2-methyl-2H-indazol- tetrazol-1-yl chloro 5-yl 21 R 1,2,3,4- 2-fluoro, 3- H, H 2H- tetrazol-1-yl chloro benzo[d][1,2,3]triazol- 5-yl 22 S* 1,2,3,4- 2-fluoro, 3- H, H 2-(difluoro-methyl)- tetrazol-1-yl chloro 2H-indazol-5-yl 23 R* 1,2,3,4- 2-fluoro, 3- H, H 2-(difluoro-methyl)- tetrazol-1-yl chloro 2H-indazol-5-yl 26 RAC 1,2,3,4- 2-fluoro, 3- H, H 2-carboxy-3-fluoro- tetrazol-1-yl chloro indol-5-yl 27 RAC 1,2,3,4- 2-fluoro, 3- H, S- 2H-indazol-5-yl tetrazol-1-yl chloro methoxy 28 RAC 1,2,3,4- 2-fluoro, 3- H, S- quinoxalin-6-yl tetrazol-1-yl chloro methoxy 29 RAC 1,2,3,4- 2-fluoro, 3- H, S- quinolin-6-yl tetrazol-1-yl chloro methoxy 30 RAC 1,2,3,4- 2-fluoro, 3- H, H 2-hydroxy-isoindolin- tetrazol-1-yl chloro 5-yl-1-one 31 RAC 1,2,3,4- 2-fluoro, 3- H, H 2-(N-hydroxy, N- tetrazol-1-yl chloro methyl-amino- carbonyl)-indol-5-yl 43 RAC 1,2,3,4- 2-fluoro, 3- H, R- 2H-indazol-5-yl tetrazol-1-yl chloro methoxy 44 RAC 1,2,3,4- 2-fluoro, 3- H, R- 2-methyl-2H-indazol- tetrazol-1-yl chloro methoxy 5-yl 45 RAC 1,2,3,4- 2-fluoro, 3- H, R- quinolin-6-yl tetrazol-1-yl chloro methoxy 46 RAC 1,2,3,4- 2-fluoro, 3- H, R- quinoxalin-6-yl tetrazol-1-yl chloro methoxy 53 RAC 1,2,3,4- 2-fluoro, 3- H, H benzimidazol-6-yl tetrazol-1-yl chloro 54 RAC 1,2,3,4- 2-fluoro, 3- H, H benzoxazol-6-yl tetrazol-1-yl chloro 55 RAC 1,2,3,4- 2-fluoro, 3- H, H benzothiazol-6-yl tetrazol-1-yl chloro 56 RAC 1,2,3,4- 2-fluoro, 3- H, H 2H- tetrazol-1-yl chloro benzo[d][1,2,3]triazol- 5-yl 57 RAC 1,2,3,4- 2-fluoro, 3- H, H 3-hydroxy-1H- tetrazol-1-yl chloro indazol-5-yl 59 R* 1,2,3,4- 2-fluoro, 3- methyl, quinoxalin-6-yl tetrazol-1-yl chloro methyl 60 R* 1,2,3,4- 2-fluoro, 3- H, H 3-amino- tetrazol-1-yl chloro benzisoxazol-6-yl 61 S* 1,2,3,4- 2-fluoro, 3- H, H 3-amino- tetrazol-1-yl chloro benzisoxazol-6-yl 62 S* 1,2,3,4- 2-fluoro, 3- methyl, quinoxalin-6-yl tetrazol-1-yl chloro methyl 64 RAC 1,2,3,4- 2-fluoro, 3- H, H 4-hydroxy-quinolin-6- tetrazol-1-yl chloro yl-2-one 79 S* 1,2,3,4- 2-fluoro, 3- H, S*- quinoxalin-6-yl tetrazol-1-yl chloro methyl 80 R* 1,2,3,4- 2-fluoro, 3- H, S*- quinoxalin-6-yl tetrazol-1-yl chloro methyl 81 R* 1,2,3,4- 2-fluoro, 3- H, R*- quinoxalin-6-yl tetrazol-1-yl chloro methyl 82 RAC 1,2,3,4- 2-fluoro, 3- H, quinolin-6-yl tetrazol-1-yl chloro methyl 83 RAC 1,2,3,4- 2-fluoro, 3- H, 2-methyl-2H-indazol- tetrazol-1-yl chloro methyl 5-yl 84 RAC 1,2,3,4- 2-fluoro, 3- H, 2H-indazol-5-yl tetrazol-1-yl chloro methyl 85 RAC 1,2,3,4- 2-fluoro, 3- H, quinoxalin-6-yl tetrazol-1-yl chloro methyl 86 RAC 1,2,3,4- 2-fluoro, 3- H, H quinoxalin-6-yl tetrazol-1-yl chloro 87 R 1,2,3,4- 2-fluoro, 3- H, H 4-(dimethyl-amino)- tetrazol-1-yl chloro quinolin-6-yl 88 R 4-chloro- 2-fluoro, 3- H, H 4-(dimethyl-amino)- 1,2,3-triazol- chloro quinolin-6-yl 1-yl 89 R 4-(trifluoro- 2-fluoro, 3- H, H 4-(dimethyl-amino)- methyl)- chloro quinolin-6-yl 1,2,3-triazol- 1-yl 96 R 5-deutero- 2-fluoro, 3- H, H spiro[cyclopropane- 1,2,3,4- chloro 1,3′-indolin-5-yl]-2′- tetrazol-1-yl one 101 R 1,2,3,4- 2-fluoro, 3- H, H 2H-indazol-5-yl tetrazol-1-yl chloro 102 R 4-(trifluoro- 2-fluoro, 3- H, H 3-methyl-indolin-7-yl- methyl)- chloro 2-one 1,2,3-triazol- 1-yl 103 R 4-(trifluoro- 2-fluoro, 3- H, H 2-fluoro-3-carboxy- methyl)- chloro phenyl 1,2,3-triazol- 1-yl 104 R 4-(trifluoro- 2-fluoro, 3- H, H 1-carboxy-2,3- methyl)- chloro dihydro-1H-inden-6-yl 1,2,3-triazol- 1-yl 105 R 4-chloro- 2-fluoro, 3- H, H 2-methyl-2H- 1,2,3-triazol- chloro benzo[d][1,2,3]triazol- 1-yl 5-yl 106 R 4-(trifluoro- 2-fluoro, 3- H, H 2-methyl-2H- methyl)- chloro benzo[d][1,2,3]triazol- 1,2,3-triazol- 5-yl 1-yl 110 RAC 1,2,3,4- 2-fluoro, 3- H, S- 2-methyl-2H-indazol- tetrazol-1-yl chloro methoxy 5-yl

1 RAC 1,2,3,4- 2-fluoro, 3- H, H 2-(1R*-hydroxy- tetrazol-1-yl chloro ethyl)-quinoxalin-6-yl 2 RAC 1,2,3,4- 2-fluoro, 3- H, H 2-(1S*-hydroxy- tetrazol-1-yl chloro ethyl)-quinoxalin-6-yl 3 RAC 1,2,3,4- 2-fluoro, 3- H, H 2-(2-methoxy-ethyl)- tetrazol-1-yl chloro 2H-indazol-5-yl 4 RAC 1,2,3,4- 2-fluoro, 3- H, H 1 -(2-methoxy-ethyl)- tetrazol-1-yl chloro 1H-indazol-5-yl 90 RAC 1,2,3,4- 2-fluoro, 3- H, H 2-(2-hydroxy-n-prop- tetrazol-1-yl chloro 2-yl)-benzthiazol-5-yl 91 RAC 1,2,3,4- 2-fluoro, 3- H, H 2-(1R*-hydroxy- tetrazol-1-yl chloro ethyl)-benzthiazol-5- yl 92 RAC 1,2,3,4- 2-fluoro, 3- H, H 2-(1S*-hydroxy- tetrazol-1-yl chloro ethyl)-benzthiazol-5- yl 107 RAC 4-(trifluoro- 2-fluoro, 3- H, H 2-(ethoxy-ethoxy)- methyl)- chloro quinolin-6-yl 1,2,3-triazol- 1-yl

As used herein, the “*” symbol or notation shall denote the presence of a stereogenic center.

Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers or stereoisomers. It is to be understood that all such isomers/stereoisomers and mixtures thereof are encompassed within the scope of the present invention. It is further understood that atropisomers (a specific type of stereoisomer resulting from steric or other hinderances to rotation) are also encompassed within the scope of the present invention.

Preferably, wherein the compound is present as an enantiomer, the enantiomer is present at an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%. Similarly, wherein the compound is present as a diastereomer or stereoisomer, the diastereomer or stereoisomer is present at a diastereomeric or stereoisomeric excess of greater than or equal to about 80%, more preferably, at a diastereomeric or stereoisomeric excess of greater than or equal to about 90%, more preferably still, at a diastereomeric or stereoisomeric excess of greater than or equal to about 95%, more preferably still, at a diastereomeric or stereoisomeric excess of greater than or equal to about 98%, most preferably, at a diastereomeric or stereoisomeric excess of greater than or equal to about 99%.

In some embodiments, the present invention is directed to compounds of formula (A) and/or compounds of formula (I) in an stereoisomeric excess of one or more stereocenters in the R- or S-stereo-configuration. In some embodiments of the present invention, the compound of formula (A) and/or compounds of formula (I) is present in a stereoisomeric excess of one or more of the stereocenters in the R- or S-stereo-configuration of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99%. Preferably the compound of formula (A) and/or compounds of formula (I) is present in a stereoisomeric excess of one or more stereocenters in the R- or S-stereo-configuration of greater than or equal to about 80%, preferably greater than or equal to about 90%, more preferably greater than or equal to about 93%, more preferably greater than or equal to about 95%, more preferably greater than or equal to about 97%, more preferably greater than or equal to about 98%, more preferably greater than or equal to about 99%.

Furthermore, some of the crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

As used herein, unless otherwise noted, the term “isotopologues” shall mean molecules that differ only in their isotopic composition. More particularly, an isotopologue of a molecule differs from the parent molecule in that it contains at least one atom which is an isotope (i.e. has a different number of neutrons from its parent atom).

For example, isotopologues of water include, but are not limited to, “light water” (HOH or H₂O), “semi-heavy water” with the deuterium isotope in equal proportion to protium (HDO or ¹H²HO), “heavy water” with two deuterium isotopes of hydrogen per molecule (d₂O or ²H₂O), “super-heavy water” or tritiated water (T₂O or ³H₂O), where the hydrogen atoms are replaced with tritium (³H) isotopes, two heavy-oxygen water isotopologues (H₂ ¹⁸O and H₂ ¹⁷O) and isotopologues where the hydrogen and oxygen atoms may each independently be replaced by isotopes, for example the doubly labeled water isotopologue d₂ ¹⁸O.

It is intended that within the scope of the present invention, any one or more element(s), in particular when mentioned in relation to a compound of formula (A) and/or compound of formula (I), shall comprise all isotopes and isotopic mixtures of said element(s), either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.

For example, a reference to hydrogen includes within its scope ¹H, ²H (D), and ³H (T). Similarly, references to carbon and oxygen include within their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁸O and ¹⁸O. The isotopes may be radioactive or non-radioactive. Radiolabelled compounds of formula (I) may comprise one or more radioactive isotope(s) selected from the group of ³H, ¹¹C, ¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, the radioactive isotope is selected from the group of ³H, ¹¹C and ¹⁸F.

As used herein, unless otherwise noted, the term “isotopomer” shall mean isomers with isotopic atoms, having the same number of each isotope of each element but differing in their position. Isotopomers include both constitutional isomers and stereoisomers solely based on isotopic location. For example, CH₃CHDCH₃ and CH₃CH₂CH₂D are a pair of constitutional isotopomers of n-propane; whereas (R)—CH₃CHDOH and (S)—CH₃CHDOH or (Z)—CH₃CH═CHD and (E)-CH₃CH═CHD are examples of isotopic stereoisomers of ethanol and n-propene, respectively.

It is further intended that the present invention includes the compounds described herein, including all isomers thereof (including, but not limited to stereoisomers, enantiomers, diastereomers, tautomers, isotopologues, isotopomers, and the like).

Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a “phenyl-(C₁-C₆alkylene)-amino-carbonyl-(C₁-C₆alkylene)-” substituent refers to a group of the formula

As used herein, unless otherwise noted, the term “isolated form” shall mean that the compound is present in a form which is separate from any solid mixture with another compound(s), solvent system or biological environment. In an embodiment of the present invention, the compound of formula (A) or compound of formula (I) is present in an isolated form.

As used herein, unless otherwise noted, the term “substantially pure form” shall mean that the mole percent of impurities in the isolated compound is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably, less than about 0.1 mole percent. In an embodiment of the present invention, the compound of formula (A) or compound of formula (I) is present as a substantially pure form.

As used herein, unless otherwise noted, the term “substantially free of a corresponding salt form(s)” when used to described the compound of formula (A) or compound of formula (I) shall mean that mole percent of the corresponding salt form(s) in the isolated base of formula (A) or compound of formula (I), respectively is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably less than about 0.1 mole percent. In an embodiment of the present invention, the compound of formula (A) or compound of formula (I) is present in a form which is substantially free of corresponding salt form(s).

2. General Synthesis Schemes

Compounds of formula (A) and compounds of formula (I) of the present invention may be prepared as described in the general synthesis schemes and Examples which follow hereinafter, selecting and substituting suitable reagents and conditions, as would be well within the skill of persons versed in the art. Additionally, the preparation of any starting materials used in the schemes and synthesis examples which follow hereinafter is well within the skill of persons versed in the art.

One skilled in the art will recognize that although the synthesis schemes which follow herein describe the preparation of compounds of formula (I) and intermediates in the synthesis of compounds of formula (I), said synthesis methods may be applied to the preparation of compounds of formula (A) (as well as other stereo-isomers of the compound of formula (A)) by substituting a suitably substituted racemic (or stereo-isomerically enriched) starting materials and/or reagents.

Compounds of formula (I) may be prepared as described in Scheme 1, below.

Accordingly, a suitably substituted compound of formula (V), a known compound or compound prepared for example as described in the Schemes and Examples which follow hereinafter, is reacted with a suitably substituted compound of formula (VI), a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent such as EDCl, HATU, PyBOP, and the like; in the presence of a suitably selected organic amine base such as pyridine, DIEA, Et₃N, and the like; neat or in a suitably selected solvent such as DMF, DCM, THF, and the like; to yield the corresponding compound of formula (I).

Compounds of formula (V) (preferably compounds of formula (V) wherein R¹ is other than 1,2,3,4-tetrazol-1-yl) may be prepared as described in Scheme 2, below.

Accordingly, a suitably substituted compound of formula (X), wherein A¹ is C₁₋₄alkyl, preferably methyl or ethyl, a known compound or compound prepared according to methods such as those described in the Schemes and Examples which follow hereinafter, is reacted with a suitably selected oxygen protecting reagent such as 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide, trifluoromethanesulfonic anhydride, and the like; in the presence of a suitably selected organic amine base such as TEA, pyridine, DIEA, and the like; in a suitably selected solvent such as DCM, THF, and the like; to yield the corresponding compound of formula (XI), wherein PG¹ is the corresponding oxygen protecting group.

The compound of formula (XI) is reacted with a suitably substituted compound of formula (XII), wherein —B(OR)₂ is for example, —B(OH)₂, —B(OCH₃)₂,

and the like, a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent such as Pd(dppf)Cl₂, Pd(PPh₃)₄, Pd(OAc)₂, and the like; in the presence of a suitably selected base such as K₂CO₃, Cs₂CO₃, K₃PO₄, and the like; in a suitably selected solvent or mixture of solvents such as a mixture of 1,4-dioxane and water, DMF, toluene/water, and the like; at an elevated temperature, such as about 80° C.; to yield the corresponding compound of formula (Va).

Compounds of formula (V) wherein R¹ is 1,2,3,4-tetrazol-1-yl may be prepared as described in Scheme 3, below.

Accordingly, a suitably substituted compound of formula (Vb), prepared for example as described in Scheme 2 above, is reacted according to known methods to convert the A¹-alkylester to the corresponding carboxy group; to yield the corresponding compound of formula (XIII). For example, the compound of formula (Vb) may be reacted with LiOH, in a mixture of THF, methanol and water.

The compound of formula (XIII) is reacted with a suitably selected reagent such as TMSN₃, NaN₃, 1-butyl-3-methylimidazolium azide, KN₃, and the like; in the presence of trimethoxymethane, and the like; in a suitably selected solvent such as AcOH, CH₃SO₃H, CF₃SO₃H, and the like; to yield the corresponding compound of formula (Vc).

Compounds of formula (V) wherein R¹ is 4-(trifluoromethyl)-1,2,3-triazol-1-yl may be prepared as described in Scheme 4, below.

Accordingly, a suitably substituted compound of formula (Vb), prepared for example as described in Scheme 2 above, is reacted with tert-butyl nitrite, a known compound; in the presence of a suitably selected reagent such as TMSN₃, NaN₃, and the like; in a suitably selected solvent such as ACN, water, EtOAc, and the like; to yield the corresponding compound of formula (XIV)

The compound of formula (XIV) is reacted with 4,4,4-trifluorobut-2-ynoic acid, a known compound; in the presence of a suitably selected coupling agent such as Cu₂O, CuI, and the like; in a suitably selected solvent such as acetonitrile, DCM, THF, and the like; at an elevated temperature, for example at reflux temperature; to yield the corresponding compound of formula (XV).

The compound of formula (XV) is reacted according to known methods to convert the A¹-alkylester to the corresponding carboxy group; to yield the corresponding compound of formula (Vd). For example, the compound of formula (XV) may be reacted with LiOH, in a mixture of THF, methanol and water.

Compounds of formula (X) wherein R³ and R⁴ are hydrogen are known compound or compounds which may be prepared by known methods. Compounds of formula (X) wherein R³ and R⁴ are hydrogen may alternatively be prepared as described in Intermediate Example A, Steps 1-6, and Intermediate Example C, Steps 1-6, which follows hereinafter.

Compounds of formula (X) wherein one or both of R³ and/or R⁴ are other than hydrogen may be prepared for example, as described in Scheme 5 below.

Accordingly, a suitably substituted compound of formula (XVI), wherein A¹ is C₁₋₄alkyl, preferably methyl or ethyl, and wherein PG² is a suitably selected nitrogen protecting group such as Boc, benzyl, PMB, and the like, a known compound or compound prepared by known methods, is reacted with SUPER-HYDRIDE®, a known compound; in a suitably selected solvent such as THF, 1,4-dioxane, and the like; at a reduced temperature, for example at about −78° C.; and then reacted with a suitably selected catalyst such as p-TsOH, and the like; in a suitably selected solvent such as MeOH, and the like; to yield the corresponding compound of formula (XVII).

The compound of formula (XVII) is reacted with allyltrimethylsilane, a known compound; in the presence of a suitably selected Lewis acid such as BF₃.Et₂O, TiCl₄, and the like; in a suitably selected solvent such as diethyl ether, THF, DCM, and the like; at a reduced temperature, for example at about −40° C.; to yield the corresponding compound of formula (XVIII).

The compound of formula (XVIII) is de-protected according to known methods; to yield the corresponding compound of formula (XIX). For example, the compound of formula (XVIII) may be reacted with a suitably selected acid such as HCl; in a suitably selected solvent such as 1,4-dioxane.

The compound of formula (XIX) is reacted with acryloyl chloride, a known compound; in the presence of a suitably selected organic amine base such as TEA, pyridine, DIEA, and the like; in a suitably selected solvent such as THF, DCM, DMF, and the like; at a reduced temperature, for example at about −78° C.; to yield the corresponding compound of formula (XX).

The compound of formula (XX) is reacted with a suitably selected catalyst such as Grubb's 2^(nd) Generation Catalyst, Grubb^(3rd) Generation Catalyst, and the like; in a suitably selected solvent such a DCM, THF, toluene, and the like; at an elevated temperature, for example at about 45° C.; to yield the corresponding compound of formula (XXI).

The compound of formula (XXI) is reacted with a suitably selected hydroboronating agent such as bis(pinacolato)diboron, and the like; in the presence of a suitably selected copper reagent such as CuCl, and the like; in the presence of a suitably selected ligand such as BINAP, and the like; in the presence of a suitably selected base such a NaOt-Bu, and the like; in a suitably selected solvent or mixture of solvents, such as a mixture of THF and methanol, and the like; and then reacted with peroxide such as 30% H₂O₂ to yield the corresponding compound of formula (XXII).

The compound of formula (XXII) is reacted with a suitably selected oxidizing agent such as PCC, Dess-Martin periodonane (DMP), and the like; in a suitably selected solvent such as DCM, EtOAc, and the like; to yield the corresponding compound of formula (X-RAC).

The compound of formula (X-RAC) is then separated according to known methods as would be readily recognized by those skilled in the art, for example by chiral chromatography, chiral SFC, etc., to yield the corresponding compound of formula (X) (i.e. the corresponding S-enantiomer).

Compounds of formula (XVI) are known compounds or compounds prepared by known methods. For example, the compound of formula (XVI) wherein R³ and R⁴ are each methyl may be prepared by reacting a suitably substituted compound of formula (XXIII)

wherein A¹ is C₁₋₄alkyl, preferably methyl or ethyl, and wherein PG² is a suitably selected nitrogen protecting group such as Boc, a known compound or compound prepared by known methods, with CH₃I, in the presence of a suitable base such as LiHMDS, in a solvent such as THF; at a temperature of about −78° C.; as described in Intermediate Example D, Step 1, which follows hereinafter.

In another example, the compound of formula (XVI) wherein R³ is hydrogen and R⁴ is methyl may be prepared by reacting the compound of formula (XXIII) with tert-butoxy bis(dimethylamino)methane, in a solvent such as DME, at a temperature of about 70° C.; and then reacting the resulting compound with a H_(2(g)), in the presence of Pd/C catalyst, in a solvent such a i-PrOH; as described in Intermediate Example D, Steps 1-2, which follows hereinafter.

In another example, the compound of formula (XVI) wherein R³ is hydrogen and R⁴ is methyl may be prepared by reacting the compound of formula (XXIV)

wherein A¹ is C₁₋₄alkyl, preferably methyl or ethyl, and wherein PG² is a suitably selected nitrogen protecting group such as Boc, a known compound or compound prepared by known methods, with CH₃I, in the presence of a strong base such as NaH, in a solvent such as DMF; and then reacting the resulting compound with suitably selected oxidating reagent(s) such as RuCl₂ and NaIO₂, in a solvent mixture such as a mixture of water and ethyl acetate; as described in Intermediate Example F, Steps 1-2, which follows hereinafter.

One skilled in the art will recognize that various substituent groups and/or functional groups on said substituent groups (for example —OH, —NH₂, etc.) may be protected prior to any reaction step described above, and then de-protected at a later step in the synthesis, as would be desirable or necessary, according to methods well known to those skilled in the art.

As more extensively provided in this written description, terms such as “reacting” and “reacted” are used herein in reference to a chemical entity that is any one of: (a) the actually recited form of such chemical entity, and (b) any of the forms of such chemical entity in the medium in which the compound is being considered when named.

One skilled in the art will recognize that, where not otherwise specified, the reaction step(s) is performed under suitable conditions, according to known methods, to provide the desired product. One skilled in the art will further recognize that, in the specification and claims as presented herein, wherein a reagent or reagent class/type (e.g. base, solvent, etc.) is recited in more than one step of a process, the individual reagents are independently selected for each reaction step and may be the same of different from each other. For example wherein two steps of a process recite an organic or inorganic base as a reagent, the organic or inorganic base selected for the first step may be the same or different than the organic or inorganic base of the second step. Further, one skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.

One skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.

One skilled in the art will further recognize that the reaction or process step(s) as herein described are allowed to proceed for a sufficient period of time until the reaction is complete, as determined by any method known to one skilled in the art, for example, chromatography (e.g. HPLC). In this context a “completed reaction or process step” shall mean that the reaction mixture contains a significantly diminished amount of the starting material(s)/reagent(s) and a significantly reduced amount of the desired product(s), as compared to the amounts of each present at the beginning of the reaction.

To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about”. It is understood that whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.

To provide a more concise description, some of the quantitative expressions herein are recited as a range from about amount X to about amount Y. It is understood that wherein a range is recited, the range is not limited to the recited upper and lower bounds, but rather includes the full range from about amount X through about amount Y, or any amount or range therein.

Examples of suitable solvents, bases, reaction temperatures, and other reaction parameters and components are provided in the detailed descriptions which follow herein. One skilled in the art will recognize that the listing of said examples is not intended, and should not be construed, as limiting in any way the invention set forth in the claims which follow thereafter.

As used herein, unless otherwise noted, the term “leaving group” shall mean a charged or uncharged atom or group which departs during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.

During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

As used herein, unless otherwise noted, the term “nitrogen protecting group” shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction. Suitable nitrogen protecting groups include, but are not limited to carbamates—groups of the formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl, benzyl, phenylethyl, CH₂═CH—CH₂—, and the like; amides—groups of the formula —C(O)—R′ wherein R′ is for example methyl, phenyl, trifluoromethyl, and the like; N-sulfonyl derivatives—groups of the formula —SO₂—R″ wherein R″ is for example tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogen protecting groups may be measured in texts such as T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

As used herein, unless otherwise noted, the term “oxygen protecting group” shall mean a group which may be attached to an oxygen atom to protect said oxygen atom from participating in a reaction and which may be readily removed following the reaction. Suitable oxygen protecting groups include, but are not limited to, acetyl, benzoyl, t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, THP, and the like. Other suitable oxygen protecting groups may be measured in texts such as T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

Additionally, chiral HPLC against a standard may be used to determine percent enantiomeric excess (% ee). The enantiomeric excess may be calculated as follows

[(Rmoles−Smoles)/(Rmoles+Smoles)]×100%

where Rmoles and Smoles are the R and S mole fractions in the mixture such that Rmoles+Smoles=1. The enantiomeric excess may alternatively be calculated from the specific rotations of the desired enantiomer and the prepared mixture as follows:

ee=([α−obs]/[α−max])×100.

The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

3. Pharmaceutical Compositions

The present invention further comprises pharmaceutical compositions containing a compound of formula (A) or compound of formula (I) with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like, for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.

To prepare the pharmaceutical compositions of this invention, one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like, for solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.01 mg to about 1000 mg or any amount or range therein, and may be given at a dosage of from about 0.05 mg/day to about 1000 mg/day, or any amount or range therein, about 0.1 mg/day to about 500 mg/day, or any amount or range therein, preferably from about 1 mg/day to about 300 mg/day, or any amount or range therein.

The dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these pre-formulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid pre-formulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.01 mg to about 1,000 mg, or any amount or range therein, of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form yielding the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of the treatment and/or prophylaxis of thromboembolic disorders described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.01 mg and about 1000 mg of the compound, or any amount or range therein, preferably from about 0.05 mg to about 500 mg of the compound, or any amount or range therein, more preferably from about 0.1 mg to about 500 mg of the compound, or any amount or range therein, more preferably from about 0.1 mg to about 500 mg of the compound, or any amount or range therein, more preferably from about 10 mg to about 500 mg of the compound, or any amount or range therein, and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

The liquid forms may include suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.

To prepare a pharmaceutical composition of the present invention, a compound of formula (A) or compound of formula (I) as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be measured in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain. Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

Compounds of the present invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment or prophylaxis of thromboembolic disorders, inflammatory disorders or diseases or conditions in which plasma kallikrein activity is implicated is required.

The daily dosage of the products may be varied over a wide range from about 0.01 mg to about 1,000 mg per adult human per day, or any amount or range therein. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug may be ordinarily supplied at a dosage level of from about 0.005 mg/kg to about 10 mg/kg of body weight per day, or any amount or range therein. Preferably, the range is from about 0.01 to about 5.0 mg/kg of body weight per day, or any amount or range therein, more preferably, from about 0.1 to about 1.0 mg/kg of body weight per day, or any amount or range therein, more preferably, from about 0.1 to about 0.5 mg/kg of body weight per day, or any amount or range therein. The compounds may be administered on a regimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.

One skilled in the art will recognize that, both in vivo and in vitro trials using suitable, known and generally accepted cell and/or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

One skilled in the art will further recognize that human clinical trials including first-in-human, dose ranging and efficacy trials, in healthy patients and/or those suffering from a given disorder, may be completed according to methods well known in the clinical and medical arts.

4. Utility

The compounds of the present invention are useful for the treatment and/or prophylaxis of thromboembolic disorders, inflammatory disorders and diseases or conditions in which factor XIa and/or plasma kallikrein activity is implicated.

In some embodiments, the present invention is directed to methods for the treatment and/or prophylaxis of a thromboembolic disorder comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of a least one of the compounds as described herein, or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

As used herein, the term “thromboembolic disorders” includes arterial cardiovascular thromboembolic disorders, venous cardiovascular or cerebrovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart or in the peripheral circulation. The term “thromboembolic disorders” as used herein also includes specific disorders selected from, but not limited to, unstable angina or other acute coronary syndromes, atrial fibrillation, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis. The medical implants or devices include, but are not limited to: prosthetic valves, artificial valves, indwelling catheters, stents, blood oxygenators, shunts, vascular access ports, ventricular assist devices and artificial hearts or heart chambers, and vessel grafts. The procedures include, but are not limited to: cardiopulmonary bypass, percutaneous coronary intervention, and hemodialysis. In some embodiments, the term “thromboembolic disorders” includes acute coronary syndrome, stroke, deep vein thrombosis, and pulmonary embolism. In some embodiments, the “thromboembolic disorders” include hereditary angioedema (HAE) and diabetic macular edema (DME).

In some embodiments, the present invention is directed to methods for the treatment and/or prophylaxis of an inflammatory disorder comprising: administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof. Examples of the inflammatory disorders include, but are not limited to, sepsis, acute respiratory distress syndrome, and systemic inflammatory response syndrome.

In some embodiments, the present invention is directed to methods for the treatment and/or prophylaxis of a disease or condition in which plasma kallikrein activity is implicated, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof. The diseases or conditions in which plasma kallikrein activity is implicated include, but are not limited to, impaired visual acuity, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, and cardiopulmonary bypass surgery.

In some embodiments, the present invention provides a method for treating the primary prophylaxis of a thromboembolic disorder. In some embodiments, the present invention provides a method for the primary prophylaxis of a thromboembolic disorder wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis. In another embodiment, the present invention provides a method for the primary prophylaxis of a thromboembolic disorder, wherein the thromboembolic disorder is selected from acute coronary syndrome, stroke, venous thrombosis, and thrombosis resulting from medical implants and devices.

In some embodiments, the present invention provides a method for the secondary prophylaxis of a thromboembolic disorder. In some embodiments, the present invention provides a method for the secondary prophylaxis of a thromboembolic disorder. wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, recurrent myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis. In another embodiment, the present invention provides a method for the secondary prophylaxis of a thromboembolic disorder, wherein the thromboembolic disorder is selected from acute coronary syndrome, stroke, atrial fibrillation and venous thrombosis.

One skilled in the art will recognize that wherein the present invention is directed to methods of prophylaxis, the subject in need thereof (i.e. a subject in need of prophylaxis) shall include any subject or patient (preferably a mammal, more preferably a human) who has experienced or exhibited at least one symptom of the disorder, disease or condition to be prevented. Further, a subject in need thereof may additionally be a subject (preferably a mammal, more preferably a human) who has not exhibited any symptoms of the disorder, disease or condition to be prevented, but who has been deemed by a physician, clinician or other medical profession to be at risk of developing said disorder, disease or condition. For example, the subject may be deemed at risk of developing a disorder, disease or condition (and therefore in need of prophylaxis or prophylactic treatment) as a consequence of the subject's medical history, including, but not limited to, family history, pre-disposition, co-existing (comorbid) disorders or conditions, genetic testing, and the like.

The compounds of the present invention are preferably administered alone to a mammal in a therapeutically effective amount. However, the compounds of the invention can also be administered in combination with an additional therapeutic agent, as defined below, to a mammal in a therapeutically effective amount. When administered in a combination, the combination of compounds is preferably, but not necessarily, a synergistic combination. Synergy, for example, may occur when the effect (in this case, inhibition of the desired target) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased anticoagulant effect, or some other beneficial effect of the combination compared with the individual components. Possible favorable outcomes of treatment with a synergistic combination include, but are not limited to, (a) increased efficacy of the therapeutic effect, (b) ability to administer decreased dosage while increasing or maintaining efficacy (which in turn may also result in decreased toxicity and/or adverse side effects), (c) minimized or slowed development of drug resistance, (d) selective synergism against the biological target (or efficacy synergism) versus host (toxicity antagonism).

In some embodiments of the present invention, the compound of formula (I) may be administered in combination with one or more anticoagulant, anti-thrombin agent, anti-platelet agent, fibrinolytic, hypolipidemic agent, antihypertensive agent, and/or anti-ischemic agent. Suitable examples include, but are not limited to warfarin, heparin, aprotinin, a synthetic pentasaccharide, a boroarginine derivative, a boropeptide, heparin, hirudin, argatroban, a thromboxane-A2-receptor antagonist, a thromboxane-A2-synthetase inhibitor, a PDE-III inhibitor, a PDE V inhibitor, an ADP receptor antagonist, an antagonist of the purinergic receptor P2Y1, an antagonist of the purinergic receptor P2Y12, tissue plasminogen activator and modified forms thereof, anistreplase, urokinase, streptokinase, tenecteplase, lanoteplase, a PAI-I inhibitor, an alpha-2-antiplasmin inhibitor, an anisoylated plasminogen streptokinase activator complex, a HMG-CoA reductase inhibitor, a squalene synthetase inhibitor, a fibrate, a bile acid sequestrant, an ACAT inhibitor, a MTP inhibitor, a lipooxygenase inhibitor, a cholesterol absorption inhibitor, a cholesterol ester transfer protein inhibitor, an alpha adrenergic blocker, a beta adrenergic blocker, a calcium channel blocker, a diuretic, a renin inhibitor, an angiotensin-converting enzyme inhibitor, an angiotensin-II-receptor antagonist, an ET receptor antagonist, a Dual ET/A11 antagonist, a neutral endopeptidase inhibitor, a vasopeptidase inhibitor, a Class I agent, a Class II agent, a Class III agent, a Class IV agent, an IAch inhibitor, an IKur inhibitor and a cardiac glycoside.

By “administered in combination” or “combination therapy” it is meant that the compound of the present invention and one or more additional therapeutic agents are administered concurrently or consecutively to the subject (preferably mammal, more preferably human) being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. Chou, Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies, Pharmacol Rev., 2006, vol. 58, 621-681.

5. Combination Therapy

One or more additional pharmacologically active agents may be administered in combination with the compounds of the invention. The additional active agent (or agents) is intended to mean a pharmaceutically active agent (or agents) that is active in the body, including pro-drugs that convert to pharmaceutically active form after administration, which is different from the compound of formula (I), and also includes free-acid, free-base and pharmaceutically acceptable salts of said additional active agents when such forms are sold commercially or are otherwise chemically possible. Generally, any suitable additional active agent or agents, including but not limited to antihypertensive agents, additional diuretics, anti-atherosclerotic agents such as a lipid modifying compound, anti-diabetic agents and/or anti-obesity agents may be used in any combination with the compound of formula (I) in a single dosage formulation (a fixed dose drug combination), or may be administered to the patient in one or more separate dosage formulations which allows for concurrent or sequential administration of the active agents (co-administration of the separate active agents).

Examples of additional active agents which may be employed include but are not limited to angiotensin converting enzyme inhibitors (e.g, alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril); angiotensin receptor antagonists also known as angiotensin receptor blockers or ARBs (e.g., losartan i.e., COZAAR®, valsartan, candesartan, olmesartan, telmesartan, eprosartan, irbesartan and any of these drugs used in combination with hydrochlorothiazide such as HYZAAR®); diuretics, e.g. hydrochlorothiazide (HCTZ); potassium sparing diuretics such as amiloride HCl, spironolactone, epleranone, triamterene, each with or without HCTZ; neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon); aldosterone antagonists; aldosterone synthase inhibitors; renin inhibitors (e.g. urea derivatives of di- and tri-peptides (See U.S. Pat. No. 5,116,835), amino acids and derivatives (U.S. Pat. Nos. 5,095,119 and 5,104,869), amino acid chains linked by non-peptidic bonds (U.S. Pat. No. 5,114,937), di- and tri-peptide derivatives (U.S. Pat. No. 5,106,835), peptidyl amino diols (U.S. Pat. Nos. 5,063,208 and 4,845,079) and peptidyl beta-aminoacyl aminodiol carbamates (U.S. Pat. No. 5,089,471); also, a variety of other peptide analogs as disclosed in the following U.S. Pat. Nos. 5,071,837; 5,064,965; 5,063,207; 5,036,054; 5,036,053; 5,034,512 and 4,894,437, and small molecule renin inhibitors (including diol sulfonamides and sulfinyls (U.S. Pat. No. 5,098,924), N-morpholino derivatives (U.S. Pat. No. 5,055,466), N-heterocyclic alcohols (U.S. Pat. No. 4,885,292) and pyrrolimidazolones (U.S. Pat. No. 5,075,451); also, pepstatin derivatives (U.S. Pat. No. 4,980,283) and fluoro- and chloro-derivatives of statone-containing peptides (U.S. Pat. No. 5,066,643); enalkrein; RO 42-5892 (CAS Registry Number 126222-34-2, also known as remikiren); A 65317 (CAS Registry Number 119625-78-4); CP 80794 (CAS Registry Number 119625-78-4, also known as terlakiren)); ES 1005 (CAS Registry Number 115404-79-0); ES 8891 (CAS Registry Number 129445-88-1); SQ 34017 (CAS Registry Number 695226-77-8); aliskiren (2(S),4(S),5(S),7(S)—N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamide hemifumarate); endothelin receptor antagonists; vasodilators (e.g. nitroprusside); calcium channel blockers (e.g., amlodipine, nifedipine, verapamil, diltiazem, felodipine, gallopamil, niludipine, nimodipine, nicardipine); potassium channel activators (e.g., nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam); sympatholitics; beta-adrenergic blocking drugs (e.g., acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, metoprolol, metoprolol tartate, nadolol, propranolol, sotalol, timolol); alpha adrenergic blocking drugs (e.g., doxazocin, prazocin or alpha methyldopa); central alpha adrenergic agonists; peripheral vasodilators (e.g. hydralazine); lipid lowering agents, e.g., HMG-CoA reductase inhibitors such as simvastatin and lovastatin which are marketed as ZOCOR® and MEVACOR® in lactone pro-drug form and function as inhibitors after administration, and pharmaceutically acceptable salts of dihydroxy open ring acid HMG-CoA reductase inhibitors such as atorvastatin (particularly the calcium salt sold in LIPITOR®), rosuvastatin (particularly the calcium salt sold in CRESTOR®), pravastatin (particularly the sodium salt sold in PRAVACHOL®), and fluvastatin (particularly the sodium salt sold in LESCOL®); a cholesterol absorption inhibitor such as ezetimibe (ZETIA®), and ezetimibe in combination with any other lipid lowering agents such as the HMG-CoA reductase inhibitors noted above and particularly with simvastatin (VYTORIN®) or with atorvastatin calcium; niacin in immediate-release or controlled release forms, and particularly niacin in combination with a DP antagonist such as laropiprant (TREDAPTIVE®) and/or with an HMG-CoA reductase inhibitor; niacin in immediate-release or controlled release forms, and particularly niacin in combination with a DP antagonist such as laropiprant (TREDAPTIVE®) and/or with an HMG-CoA reductase inhibitor; niacin receptor agonists such as acipimox and acifran, as well as niacin receptor partial agonists; metabolic altering agents including insulin sensitizing agents and related compounds for the treatment of diabetes such as biguanides (e.g., metformin), meglitinides (e.g., repaglinide, nateglinide), sulfonylureas (e.g., chlorpropamide, glimepiride, glipizide, glyburide, tolazamide, tolbutamide), thiazolidinediones also referred to as glitazones (e.g., pioglitazone, rosiglitazone), alpha glucosidase inhibitors (e.g., acarbose, miglitol), dipeptidyl peptidase inhibitors, (e.g., sitagliptin (JANUVIA®), alogliptin, vildagliptin, saxagliptin, linagliptin, dutogliptin, gemigliptin), ergot alkaloids (e.g., bromocriptine), combination medications such as JANUMET® (sitagliptin with metformin), and injectable diabetes medications such as exenatide and pramlintide acetate; or with other drugs beneficial for the prevention or the treatment of the above-mentioned diseases including but not limited to diazoxide; and including the free-acid, free-base, and pharmaceutically acceptable salt forms of the above active agents where chemically possible. Compounds which can be alternatively or additionally administered in combination with the compounds of the present invention include, but are not limited to, anticoagulants, anti-thrombin agents, anti-platelet agents, fibrinolytics, hypolipidemic agents, antihypertensive agents, and anti-ischemic agents.

Anticoagulant agents (or coagulation inhibitory agents) that may be used in combination with the compounds of this invention include warfarin, heparin (either unfractionated heparin or any commercially available low molecular weight heparin, for example enoxaparin and dalteparin), aprotinin, synthetic pentasaccharide inhibitors of Factor Xa such as fondaparinux and idraparinux, direct Factor Xa inhibitors such as rivaroxaban, apixaban, betrixaban, edoxaban, otamixaban, direct acting thrombin inhibitors including hirudin, dabigatran, argatroban, ximelagatran, melagatran, lepirudin, desirudin, and bivalirudin, as well as other factor VIIa inhibitors, VIIIa inhibitors, DCa inhibitors, Xa inhibitors, XIa inhibitors, fibrinogen receptor antagonists (including abciximab, eptifibatide and tirofiban), TAFI inhibitors, and others known in the art. Factor DCa inhibitors include synthetic active-site blocked competitive inhibitors, oral inhibitors and RNA aptamers. These are described in Howard, E L, Becker K C, Rusconi, C P, Becker R C. Factor IXa Inhibitors as Novel Anticoagulents. Arterioscler Thromb Vasc Biol, 2007; 27: 722-727.

The term “anti-platelet agents” or “platelet inhibitory agents”, as used herein, denotes agents that inhibit platelet function, for example, by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicylic acid or ASA), and piroxicam are preferred. Other suitable platelet inhibitory agents include IIb/IIIa antagonists (e.g., tirofiban, eptifibatide, and abciximab), thromboxane-A2-receptor antagonists (e.g., ifetroban), thromboxane-A2-synthetase inhibitors, phosphodiesterase-III (PDE-III) inhibitors (e.g., dipyridamole, cilostazol), and PDE V inhibitors (such as sildenafil), and pharmaceutically acceptable salts or prodrugs thereof.

The term “anti-platelet agents” or “platelet inhibitory agents”, as used herein, is also intended to include ADP (adenosine diphosphate) receptor antagonists, preferable antagonists of the purinergic receptors P2Y1 and P2Y12 with P2Y12 being even more preferred. Preferred P2Y12 receptor antagonists include ticlopidine, prasugrel, clopidogrel, elinogrel, ticagrelor and cangrelor, including pharmaceutically acceptable salts or prodrugs thereof. Clopidogrel is an even more preferred agent. Ticlopidine and clopidogrel are also preferred compounds since they are known to be gentle on the gastro-intestinal tract in use. The compounds of the present invention may also be dosed in combination with aprotinin.

The term “thrombin inhibitors” or “anti-thrombin agents”, as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-I and/or serotonin), endothelial cell activation, inflammatory reactions, and/or fibrin formation are disrupted. A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin, dabigatran and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal alpha-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term “hirudin”, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin.

The term “thrombin receptor antagonists”, also known as protease activated receptor (PAR) antagonists or PAR-1 antagonists, are useful in the treatment of thrombotic, inflammatory, atherosclerotic and fibroproliferative disorders, as well as other disorders in which thrombin and its receptor play a pathological role. Thrombin receptor antagonist peptides have been identified based on structure-activity studies involving substitutions of amino acids on thrombin receptors. In Bernatowicz et al, J Med. Chem., vol. 39, pp. 4879-4887 (1996), tetra- and pentapeptides are disclosed as being potent thrombin receptor antagonists, for example N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH₂ and N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-Arg-NH₂. Peptide thrombin receptor antagonists are also disclosed in WO 94/03479. Substituted tricyclic thrombin receptor antagonists are disclosed in U.S. Pat. Nos. 6,063,847, 6,326,380 and WO 01/96330. Other thrombin receptor antagonists include those disclosed in U.S. Pat. Nos. 7,304,078; 7,235,567; 7,037,920; 6,645,987; and EP Patent Nos. EP1495018 and EP1294714.

The term thrombolytic (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator (TPA, natural or recombinant) and modified forms thereof, anistreplase, urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factor VIIa inhibitors, PAI-I inhibitors (i.e., inactivators of tissue plasminogen activator inhibitors), alpha-2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complexes, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complexes. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase. Examples of suitable anti-arrhythmic agents for use in combination with the present compounds include: Class I agents (such as propafenone); Class II agents (such as carvedilol and propranolol); Class III agents (such as sotalol, dofetilide, aminodarone, azimilide and ibutilide); Class IV agents (such as ditiazem and verapamil); IAch inhibitors, and IKur inhibitors (e.g., compounds such as those disclosed in WO01/40231).

6. Definitions

As used herein, unless otherwise noted, “halogen” shall mean chloro, bromo, fluoro and iodo, preferably bromo, fluoro or chloro, more preferably fluoro or chloro.

As used herein, unless otherwise noted, the term “oxo” shall mean a functional group of the structure ═O (i.e. a substituent oxygen atom connected to another atom by a double bond).

As used herein, unless otherwise noted, the term “C_(X-Y)alkyl” wherein X and Y are integers, whether used alone or as part of a substituent group, include straight and branched chains containing between X and Y carbon atoms. For example, C₁₋₄alkyl radicals include straight and branched chains of between 1 and 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl.

As used herein, unless otherwise noted, the terms “—(C_(X-Y)alkylene)- and —C_(X-Y)alkylene-” wherein X and Y are integers, shall denote any C_(X-Y)alkyl carbon chain as herein defined, wherein said C_(X-Y)alkyl chain is divalent and is further bound through two points of attachment, preferably through two terminal carbon atoms.

As used herein, unless otherwise noted, the term “fluorinated C_(X-Y)alkyl” shall mean any C_(X-Y)alkyl group as defined above substituted with one or more fluoro groups, preferably one to three fluoro group. Suitably examples include, but are not limited to —CH₂F, CHF₂, —CF₃, —CH₂—CF₃, —CF₂—CH₃, —CH₂—CH₂—CH₂F, —CH₂—CH₂—CF₃, —C(CH₃)₂CF₃, —C(CF₃)₃, and the like.

As used herein, unless otherwise noted, the term “hydroxy substituted C_(X-Y)alkyl” shall mean any C_(X-Y)alkyl group as defined above substituted with one or more hydroxy (—OH) groups, preferably one to three, more preferably one to two hydroxy groups. Suitable examples include but are not limited to —CH₂OH, —CH₂CH₂OH, —CH(OH)CH₃, —CH(OH)CH₂OH, —CH₂CH₂CH₂OH, —C(CH₂OH)₃, and the like.

As used herein, unless otherwise noted, “C_(X-Y)alkoxy” wherein X and Y are integers, shall mean an oxygen ether radical of the above described straight or branched chain C_(X-Y)alkyl groups containing between X and Y carbon atoms. For example, C₁₋₄alkoxy shall include methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, iso-butyloxy, sec-butyloxy and tert-butyloxy.

As used herein, unless otherwise noted, the term “fluorinated C_(X-Y)alkoxy” shall mean any C_(X-Y)alkoxy oxygen ether radical as defined above, substituted with one or more fluoro groups, preferably one to three fluoro groups. Suitably examples include, but are not limited to —CH₂F, CHF₂, —CF₃, —CH₂—CF₃, —CF₂—CH₃, —CH₂—CH₂—CH₂F, —CH₂—CH₂—CF₃, —C(CH₃)₂CF₃, —C(CF₃)₃, and the like.

As used herein, unless otherwise noted, the term “C_(X-Y)cycloalkyl”, wherein X and Y are integers, shall mean any stable X- to Y-membered monocyclic, bicyclic, polycyclic, bridged or spiro-cyclic saturated ring system, preferably a monocyclic, bicyclic, bridged or spiro-cyclic saturated ring system. For example, the term “C₃₋₈cycloalkyl” includes, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, cyclooctyl, bicyclo[2.2.2]octan-2-yl, and the like.

As used herein, unless otherwise noted, the term “5 to 6 membered heteroaryl” shall denote any five or six membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S. Suitably examples include, but are not limited to furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thidiazolyl, tetrazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, dioxinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, and the like.

The term “5 to 6 membered nitrogen containing heteroaryl” shall denote any five or six membered monocyclic aromatic ring structure containing at least one N atom, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S. Suitably examples include, but are not limited to pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thidiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, and the like.

The term “5 membered heteroaryl” shall denote any five membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; whereas the term and “5 membered nitrogen containing heteroaryl” shall denote any five membered monocyclic aromatic ring structure containing at least N atom, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S.

The term “6 membered heteroaryl” shall denote any six membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; whereas the term and “6 membered nitrogen containing heteroaryl” shall denote any six membered monocyclic aromatic ring structure containing at least N atom, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S.

Unless otherwise noted, any heteroaryl (regardless of the number of ring atoms, the number and identity of ring heteroatoms, etc.) may be bound through any ring atom which results in a stable structure.

As used herein, unless otherwise noted, the term “5 to 6 membered heterocycloalkyl” shall denote any five or six membered monocyclic saturated or partially unsaturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S. Suitably examples include, but are not limited to piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, trithianyl, 2,5-dihydro-1,2,4-oxadiazolyl, 1,4,5,6-tetrahydropyridazinyl, and the like.

The term “5 to 6 membered nitrogen containing heterocycloalkyl” shall denote any five or six membered monocyclic saturated or partially unsaturated ring structure containing at least one N atom, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S. Suitably examples include, but are not limited to piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 2,5-dihydro-1,2,4-oxadiazolyl, 1,4,5,6-tetrahydropyridazinyl, and the like.

The term “5 membered heterocycloalkyl” shall denote any five membered monocyclic saturated or partially unsaturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; whereas the term and “5 membered nitrogen containing heterocycloalkyl” shall denote any five membered monocyclic saturated or partially unsaturated ring structure containing at least N atom, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S.

The term “6 membered heterocyloalkyl” shall denote any six membered monocyclic saturated or partially unsaturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; whereas the term and “6 membered nitrogen containing heterocyloalkyl” shall denote any six membered monocyclic saturated or partially unsaturated ring structure containing at least N atom, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S.

Unless otherwise noted, any heterocycloalkyl (regardless of the number of ring atoms, the number and identity of ring heteroatoms, etc.) may be bound through any ring atom which results in a stable structure.

As used herein, unless otherwise noted, the term “heterocyclyl” shall denote any monocyclic, saturated, partially unsaturated or aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or any saturated, partially unsaturated, partially aromatic or aromatic bicyclic, fused, bridged or spiro-cyclic ring system containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. Suitable examples include, but are not limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl, chromenyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, 2H-benzo[d][1,2,3]triazol-5-yl, and the like.

As used herein, unless otherwise noted, the term “5 to 6 membered heterocyclyl” shall denote any five to six membered monocyclic, saturated, partially unsaturated or aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S. Suitable examples include, but are not limited to furyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, isothiazolyl, dioxolanyl, pyrazolidinyl, thiadiazolyl, pyranyl, pyridinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, and the like.

As used herein, unless otherwise noted, the term “5 to 6 membered nitrogen containing heterocyclyl” shall denote any five or six membered monocyclic, saturated, partially unsaturated or aromatic ring structure containing at least one N atom, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S. Suitable examples include, but are not limited to pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isothiazolyl, pyrazolidinyl, thiadiazolyl, pyranyl, pyridinyl, morpholinyl, dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, and the like.

As used herein, unless otherwise noted, the term “5 membered heterocyclyl” shall denote any five membered monocyclic, saturated, partially unsaturated or aromatic ring structure containing at least one N atom, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; whereas the term “5 membered nitrogen containing heterocyclyl” shall denote any five membered heterocyclyl as defined herein, wherein the ring structure contains at least one N atom, and optionally contains one to three additional heteroatoms independently selected from the group consisting of O, N and S.

As used herein, unless otherwise noted, the term “6 membered heterocyclyl” shall denote any six membered monocyclic, saturated, partially unsaturated or aromatic ring structure containing at least one N atom, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; whereas the term “6 membered nitrogen containing heterocyclyl” shall denote any six membered heterocyclyl as defined herein, wherein the ring structure contains at least one N atom, and optionally contains one to three additional heteroatoms independently selected from the group consisting of O, N and S.

As used herein, unless otherwise noted, the term “9 to 10 membered nitrogen containing heterocyclyl” shall mean any nine or ten membered, saturated, partially unsaturated, partially aromatic or aromatic, bicyclic, fused, bridged or spiro-cyclic ring system containing at least one N atom, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. Suitable examples include, but are not limited to indolenyl, indolyl, isoindolyl, indolizinyl, indolinyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinolizinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, naphthyridinyl, pteridinyl, quinuclidinyl, thionaphthenyl, pyrano[3,4-b]pyrrolyl, benzopyranyl, 2H-benzo[d][1,2,3]triazol-5-yl, and the like.

The term “9 membered nitrogen containing heterocyclyl” shall mean any nine membered, saturated, partially unsaturated, partially aromatic or aromatic, bicyclic, fused, bridged or spiro-cyclic ring system containing at least one N atom, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. The term “10 membered nitrogen containing heterocyclyl” shall mean any ten membered, saturated, partially unsaturated, partially aromatic or aromatic, bicyclic, fused, bridged or spiro-cyclic ring system containing at least one N atom, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S.

Unless otherwise noted, any heterocyclyl (regardless of the number of ring atoms, the number and identity of ring heteroatoms, degree of saturation or unsaturation, etc.) may be bound through any ring atom which results in a stable structure.

When a particular group is “substituted” (e.g. C_(X-Y)alkyl, heteroaryl, etc.), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents.

With reference to substituents, the term “independently” means that when more than one of such substituents is possible, such substituents may be the same or different from each other.

For use in medicine, the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts”. Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

Representative acids which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (±)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid.

Representative bases which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

As used herein, the terms “combination” and “pharmaceutical combination” refer to either: 1) a fixed dose combination in one dosage unit form, or 2) a non-fixed dose combination, optionally packaged together for combined administration.

As used herein, unless otherwise noted, the terms “treating”, “treatment” and the like, shall include the management and care of a subject or patient, preferably a mammal, more preferably a human, for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or complications, alleviate the symptoms or complications, slow the progression of the disease or disorder, or eliminate the disease, condition, or disorder. The terms “treating” or “treatment” further include: (a) inhibiting the disease-state, i.e., arresting its development; and/or (b) relieving the disease-state, i.e., causing regression of the disease state.

As used herein, “prevention” covers the preventive treatment of a subclinical disease-state in a mammal, particularly in a human, aimed at reducing the probability of the occurrence of a clinical disease-state. Patients are selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population.

As used herein, “prophylaxis” is the protective treatment of a disease state to reduce and/or minimize the risk and/or reduction in the risk of recurrence of a disease state by administering to a patient a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, isotopologue, a pharmaceutically acceptable salt, or a solvate thereof. Patients may be selected for prophylaxis therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population. For prophylaxis treatment, conditions of the clinical disease state may or may not be presented yet. “Prophylaxis” treatment can be divided into (a) primary prophylaxis and (b) secondary prophylaxis. Primary prophylaxis is defined as treatment to reduce or minimize the risk of a disease state in a patient that has not yet presented with a clinical disease state, whereas secondary prophylaxis is defined as minimizing or reducing the risk of a recurrence or second occurrence of the same or similar clinical disease state.

As used herein, “risk reduction” covers therapies that lower the incidence of development of a clinical disease state. As such, primary and secondary prevention therapies are examples of risk reduction.

The term “subject” as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Preferably, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.

The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.

EXAMPLES

Abbreviations used in the specification, particularly the Schemes and Examples, are as listed in the Table A, below:

TABLE A Abbreviations Ac = Acetyl (i.e. —C(O)CH₃) AcOH = Acetic Acid ACN or MeCN = Acetonitrile aq. = Aqueous BF₃•Et₂O = Boron trifluoride diethyl etherate BINAP = (2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl) Boc or BOC = tert-Butoxyloxycarbonyl (i.e. —C(O)—O—C(CH₃)₃) BPin = Bis(pinacolate)diboron BSA = Bovine Serum Albumin CHAPS = 3-[(3-Cholamidopropyl)dimethylammonio]-1- propanesulfonate DCM = Dichloromethane DEA = Diethanolamine DIEA or DIPEA = Diisopropylethyl Amine DME (biological Diabetic Macular Edema context = DME (chemistry Dimethoxyethane context = DMF = N,N-Dimethylformamide DMP or Dess Martin 3-Oxo-1λ⁵,2-benziodoxole- Periodinane = 1,1,1(3H)-triyl triacetate DMSO = Dimethylsulfoxide dppf = 1,1′-Bis(diphenylphosphino)ferrocene EA or EtOAc = Ethyl Acetate EDCI = 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide Ee = Enantiomeric Excess ER = End Point Read (assay) equiv. = Equivalents ES or ESI = Electrospray ionization Et = Ethyl EtOH = Ethanol Et₂O = Diethyl Ether Et₃N or TEA = Triethylamine FA = Formic Acid FXIa = Factor XIa Grubbs Catalyst 2^(nd) (1,3-Bis(2,4,6-trimethylphenyl)-2- generation = imidazolidinylidene)dichloro(phenylmethylene) (tricyclohexylphosphine)ruthenium Grubb's Catalyst 3^(rd) Dichloro1,3-bis(2,4,6-trimethylphenyl)-2- generation = imidazolidinylidene(benzylidene)bis(3- bromopyridine)ruthenium(II) HAE = Hereditary Angioedema HATU = (1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate Hex = Hexanes HOAc or AcOH = Acetic Acid HPLC = High Performance Liquid Chromatography IBX = 2-Iodoxybenzoic acid KIN = Kinetic Read (assay) KOAc = Potassium Acetate LC-MS or LC/MS = Liquid chromatography-mass spectrometry LDA or LiN(Pr-i)₂ = Lithium Diisopropylamide LiHMDS = Lithium bis(trimethylsilyl)amide Me = Methyl MeOH = Methanol MOM = Methoxy methyl Ms or mesyl = Methylsulfonyl (i.e. —SO₂—CH₃) MTBE = Methyl tert-Butyl Ether NaOt-Bu or t-BuONa Sodium tert-Butoxide or tert-BuONa = NMR = Nuclear Magnetic Resonance Oms or mesylate = Methanesulfonate (i.e. —O—SO₂—CH₃) Otf or triflate = Trifluoromethanesulfonyl (i.e. —O—SO—CF₃) Ots or tosylate = p-Toluenesulfonate (i.e. —O—SO₂- (p-methylphenyl)) PCC = Pyridinium chlorochromate Pd/C = Palladium on Carbon (catalyst) Pd(dppf)Cl₂ or [1,1′-Bis(diphenylphosphino)ferrocene] Palladium PdCl₂(dppf) = (II) Dichloride Pd(OAc)₂ = Palladium (II) Acetate Pd(PPh₃)₄ = Tetrakis(triphenylphosphine)palladium(0) PE = Petroleum ether Ph = Phenyl PK = Plasma Kallikrein PMB = para-Methoxybenzyl PPh₃ = Triphenylphosphine p-TsOH = Para-Toluenesulfonic Acid PBOP = (Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) RFU = Relative Fluorescence Unit SFC (purification) = Supercritical Fluid Chromatography (purification) Super-Hydride ® = 1.0M Lithium Triethylborohydride in THF TBSOTf = Tert-Butyldimethylsilyl triflate TEA or Et₃N = Triethylamine Tf or triflyl = Trifluoromethylsulfonyl (i.e. —SO₂—CF₃) TFA = Trifluoroacetic acid THF = Tetrahydrofuran THP = Tetrahydropyranyl TMS = Trimethysilyl TMSOTf = Trimethylsilyltriflate TMSCI = Trimethylsilyl Chloride TMSN₃ = Trimethylsilyl azide Tris (buffer) = 2-Amino-2-(hydroxymethyl)-1,3-propanediol Ts or tosyl = —SO₂-(p-methylphenyl) p-TsOH = para-Toluenesulfonic Acid wt % or wt % = Weight Percent

The following Examples are set forth to aid in the understanding of the invention and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.

Unless otherwise indicated in the examples, all temperature is expressed in Centigrade (° C.). All reactions were conducted under an inert atmosphere at ambient temperature unless otherwise noted. Unless otherwise specified, reaction solutions were stirred at room temperature under a N_(2(g)) or Ar_((g)) atmosphere. Reagents employed without synthetic details are commercially available or made according to known methods, for example according to literature procedures. When solutions were “concentrated to dryness”, they were concentrated using a rotary evaporator under reduced pressure, when solutions were dried, they were typically dried over a drying agent such as MgSO₄ or Na₂SO₄. Where a synthesis product is listed as having been isolated as a residue, it will be understood by those skilled in the art that the term “residue” does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.

In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

LC-MS: Unless otherwise indicated, the analytical LC-MS system used consisted of a Shimadzu LCMS-2020 with electrospray ionization (ESI) in positive ion detection mode with 20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20A PDA Detector and LCMS 2020 MS detector. The column was a HALO a C18 30*5.0 mm, 2.7 μm. The mobile phase A was water containing 0.05% TFA and mobile phase B was acetonitrile containing 0.05% TFA. The gradient was from 5% mobile phase B to 100% (95%) in 2.0 min, hold 0.7 min, then revert to 5% mobile phase B over 0.05 min and maintain for 0.25 min. The Column Oven (CTO-20AC) was operated at a 40.0° C. The flow rate was 1.5 mL/min, and the injection volume was 1 μl. PDA (SPD-M20A) detection was in the range 190-400 nm. The MS detector, which was configured with electrospray ionization as ionizable source; Acquisition mode: Scan; Nebulizing Gas Flow: 1.5 L/min; Drying Gas Flow: 15 L/min; Detector Voltage: Tuning Voltage±0.2 kv; DL Temperature: 250° C.; Heat Block Temperature: 250° C.; Scan Range: 90.00-900.00 m/z. ELSD (Alltech 3300) detector Parameters: Drift Tube Temperature: 60±5° C.; N2 Flow-Rate: 1.8±0.2 L/min. Mobile phase gradients were optimized for the individual compounds. Calculated mass corresponds to the exact mass.

Preparative HPLC: Unless otherwise noted, preparative HPLC purifications were performed with Waters Auto purification system (2545-2767) with a 2489 UV detector. The column was selected from one of the following: Waters C18, 19×150 mm, 5 μm; XBridge Prep OBD C18 Column, 30×150 mm 5 μm; XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; XBridge Shield RP18 OBD Column, 30×150 mm, 5 μm; Xselect CSH Fluoro Phenyl, 30×150 mm, 5 μm; or YMC-Actus Triart C18, 30×150 mm, 5 μm. The mobile phases consisted of mixtures of acetonitrile (5-95%) in water containing 0.1% FA or 10 mmol/L NH₄HCO₃. Flow rates were maintained at 25 mL/min, the injection volume was 1200 μL, and the UV detector used two channels 254 nm and 220 nm. Mobile phase gradients were optimized for the individual compounds.

Chiral chromatography: Chiral analytical chromatography was performed on one of Chiralpak AS, AD, Chiralcel OD, OJ Chiralpak IA, IB, IC, ID, IE, IF, IG, IH columns (Daicel Chemical Industries, Ltd.) (R,R)-Whelk-01, (S,S)-Whelk-01 columns (Regis technologies, Inc.) CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.) as noted, at different column size (50×4.6 mm, 100×4.6 mm, 150×4.6 mm, 250×4.6 mm, 50×3.0 mm, 100×3.0 mm), with percentage of either ethanol in hexane (% Et/Hex) or isopropanol in hexane (% IPA/Hex) as isocratic solvent systems, or using supercritical fluid (SFC) conditions.

Normal phase flash chromatography: Unless otherwise noted, normal phase flash column chromatography (FCC) was performed on silica gel with pre-packaged silica gel columns (such as RediSep®), using ethyl acetate (EtOAc)/hexanes, ethyl acetate (EtOAc)/Petroleum ether (b.p. 60-90° C.), CH₂Cl₂/MeOH, or CH₂Cl₂/10% 2N NH₃ in MeOH, as eluent.

¹H NMR: Unless otherwise noted, ¹H NMR spectra were acquired using 400 MHz spectrometers (or 300 MHz spectrometers) in DMSO-d₆ solutions. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (δ) are expressed in parts per million (ppm). Tetramethylsilane (TMS) was used as internal reference in DMSO-d₆ solutions, and residual CH₃OH peak or TMS was used as internal reference in CD₃OD solutions. Coupling constants (J) are reported in hertz (Hz). The nature of the shifts as to multiplicity is reported as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt (double triplet), m (multiplet), br (broad).

SYNTHESIS EXAMPLES: INTERMEDIATES Example A: (3S)-7-(6-Amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (Method A)

Step 1: 1-(Tert-butyl) 2-methyl (2S)-5-methoxypyrrolidine-1,2-dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (2.1 g, 8.63 mmol, 1.0 equiv) in THF (40 mL) was dropped lithium triethylborhydride (13 mL, 13 mmol, 1.5 equiv, 1M in THF) at −78° C. under N₂. The reaction mixture was stirred for 40 min at −78° C., then Na₂CO₃ (aq., 10 mL) was added at −78° C. and the mixture was warmed to 0° C. Hydrogen peroxide (1 mL, 30%) was added and the mixture was stirred for 30 min at room temperature. THF was removed under vacuum, and the resulting residue was extracted with diethyl ether, washed with brine, dried, and concentrated under vacuum to yield a colorless oil. The oil was dissolved into methanol (40 mL), and p-toluenesulfonic acid (149 mg, 0.86 mmol, 0.1 equiv) was added. The solution was stirred overnight at room temperature. The reaction was quenched with water and extracted with diethyl ether. The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated to yield 1-(tert-butyl) 2-methyl (2S)-5-methoxypyrrolidine-1,2-dicarboxylate as a colorless oil.

Step 2: 1-(Tert-butyl) 2-methyl (2S)-5-allylpyrrolidine-1,2-dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl (2S)-5-methoxypyrrolidine-1,2-dicarboxylate (10.0 g, 38.60 mmol, 1.0 equiv) in Et₂₀ (200 mL) were added allyltrimethylsilane (27 mL, 169.70 mmol, 4.4 equiv) and boron trifluoride etherate (6.6 g, 46.30 mmol, 1.2 equiv) at −40° C. and under a N₂ atmosphere. The reaction was stirred for 30 min at −40° C., and then warmed to room temperature and stirred for 40 min. The reaction was quenched with Na₂CO₃ (aq.) and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography (0-20% EtOAc/petroleum ether) to yield 1-(tert-butyl) 2-methyl (2S)-5-allylpyrrolidine-1,2-dicarboxylate as a yellow oil. LC/MS: mass calculated for C₁₄H₂₃NO₄: 269.16, measured: 270.20 [M+H]⁺.

Step 3: 1-(Tert-butyl) 2-methyl (2S)-5-(2-oxoethyl)pyrrolidine-1,2-dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl (2S)-5-allylpyrrolidine-1,2-dicarboxylate (7.3 g, 27.10 mmol, 1.0 equiv) in THF/H₂O (120 mL) was added OsO₄ (347 mg, 1.36 mmol, 0.05 equiv). The reaction mixture was stirred for 5 min at room temperature in the dark, and then sodium periodate (14.5 g, 67.80 mmol, 2.5 equiv) was added. The reaction was stirred for 4 h at room temperature. The reaction was quenched with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄. The solids were filtered out. The filtrate was concentrated under vacuum to yield a residue which was purified by silica gel chromatography (0-40% EA/PE) to yield 1-(tert-butyl) 2-methyl (2S)-5-(2-oxoethyl)pyrrolidine-1,2-dicarboxylate as a yellow oil. LC/MS: mass calculated for C₁₃H₂₁NO₅: 271.14, measured: 272.15 [M+H]⁺.

Step 4: 1-(Tert-butyl) 2-methyl (2S)-5-(4-ethoxy-2-hydroxy-4-oxobutyl)pyrrolidine-1,2-dicarboxylate

To a solution of tert-butyl acetate (3.9 g, 44.23 mmol, 2.0 equiv) in tetrahydrofuran (60 mL), was added lithium bis(trimethylsilyl)amide (44 mL, 44 mmol, 1.2 equiv) at −78° C. in a N₂ atmosphere, The solution was stirred for 30 min at −78° C., then 1-(tert-butyl) 2-methyl (2S)-5-(2-oxoethyl)pyrrolidine-1,2-dicarboxylate (6 g, 22.1 mmol, 1.0 equiv) was added. The reaction was stirred for 2 h at −78° C. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄. The solids were filtered out. The filtrate was concentrated under vacuum and concentrated. The resulting residue was purified by silica gel chromatography (0-80% EA/PE) to yield 1-(tert-butyl) 2-methyl (2S)-5-(4-ethoxy-2-hydroxy-4-oxobutyl)pyrrolidine-1,2-dicarboxylate as a yellow oil. LC/MS: mass calculated For C₁₇H₂₉NO₇: 359.19, measured: 360.10 [M+H]⁺.

Step 5: 1-(Tert-butyl) 2-methyl (2S)-5-(4-ethoxy-2,4-dioxobutyl)pyrrolidine-1,2-dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl (2S)-5-(4-ethoxy-2-hydroxy-4-oxobutyl)pyrrolidine-1,2-dicarboxylate (3.3 g, 9.20 mmol, 1.0 equiv) in acetonitrile (30 mL), was added IBX (10.3 g, 36.80 mmol, 4.0 equiv). The reaction was stirred overnight at 50° C. Upon cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0-80% EtOAc/petroleum ether) to yield 1-(tert-butyl) 2-methyl (2S)-5-(4-ethoxy-2,4-dioxobutyl)pyrrolidine-1,2-dicarboxylate as a yellow oil. LC/MS: mass calculated for C₁₇H₂₇NO₇: 357.18, measured: 380.15 [M+Na]⁺.

Step 6: Methyl (3S)-5,7-dioxooctahydroindolizine-3-carboxylate

To a solution of 1-(tert-butyl) 2-methyl (2S)-5-(4-ethoxy-2,4-dioxobutyl)pyrrolidine-1,2-dicarboxylate (900 mg, 2.50 mmol, 1.0 equiv) in HCl (in 1,4-dioxane, 4 M)/dichloromethane (5 mL, 1/1). The reaction was stirred for 1 h at room temperature. The solvent was removed under vacuum and the residue was dissolved in toluene (5 mL). To the resulting mixture was added sodium bicarbonate (2.1 g, 25.20 mmol, 10.0 equiv). The resulting mixture was stirred overnight at 110° C., then quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc/petroleum ether) to yield methyl (3S)-5,7-dioxooctahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C₁₀H₁₃NO₄: 211.08, measured: 212.10 [M+H]⁺.

Step 7: Methyl (3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of methyl (3S)-5,7-dioxooctahydroindolizine-3-carboxylate (370 mg, 1.75 mmol, 1.0 equiv) in dichloromethane (5 mL), were added triethylamine (355 mg, 3.50 mmol, 2.0 equiv) and N,N-bis(trifluoromethylsulfonyl)aniline (751 mg, 2.10 mmol, 1.2 equiv). The reaction was stirred overnight at room temperature. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (0-80% EA/PE) to yield methyl (3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C₁₁H₁₂F₃NO₆S: 343.03, measured: 344.05 [M+H]⁺.

Step 8: Methyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of ethyl methyl (3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (350 mg, 1.02 mmol, 1.0 equiv), (6-amino-3-chloro-2-fluorophenyl)boronic acid (232 mg, 1.20 mmol, 1.2 equiv) and potassium carbonate (282 mg, 2.04 mmol 2.0 equiv) in 1,4-dioxane/H₂O (5 mL, 10/1), was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37 mg, 0.05 mmol, 0.1 equiv). The reaction mixture was stirred for 2 h at 80° C. under N₂. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% EtOAc/petroleum ether) to yield methyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C₁₆H₁₆ClFN₂O₃: 338.08, measured: 339.10 [M+H]⁺.

Step 9: (3S)-7-(6-Amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

To a solution of methyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (210 mg, 0.62 mmol, 1.0 equiv) in THF/H₂O/MeOH (5 mL, 3/1/1), was added lithium hydroxide (124 mg, 3.10 mmol, 5.0 equiv). The reaction mixture was stirred for 1 h at room temperature. The residue was adjusted to pH 4 with HCl, then extracted with ethyl acetate and washed with brine, dried and concentrated under vacuum to yield (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid as a yellow solid. LC/MS: mass calculated for C₁₅H₁₄ClFN₂O₃: 324.07, measured: 325.05 [M+H]⁺.

Example B: Methyl (3S)-5,7-dioxooctahydroindolizine-3-carboxylate (Method B)

Step 1: Methyl (2S)-5-allylpyrrolidine-2-carboxylate

1-(tert-Butyl) 2-methyl (2S)-5-allylpyrrolidine-1,2-dicarboxylate (10 g, 37.13 mmol, 1.0 eq) was dissolved in a HCl solution (90 mL, 10.00 eq) (4 M in 1,4-dioxane). The resulting mixture was stirred for 2 h. The solvent was removed under reduced pressure to yield methyl (2S)-5-allylpyrrolidine-2-carboxylate, which was used in the next step without further purification. LC/MS: mass calculated for C₉H₁₅NO₂: 169.11, measured: 170.20 [M+H]⁺.

Step 2: Methyl (2S)-1-acryloyl-5-allylpyrrolidine-2-carboxylate

At −78° C., to a solution of methyl (2S)-5-allylpyrrolidine-2-carboxylate (6.0 g, 35.46 mmol, 1.0 eq) in THF (200 mL) was added TEA (23 mL, 177.28 mmol, 5.0 eq) followed by acryloyl chloride (3.2 g, 35.46 mmol, 1.0 eq). The resulting mixture was stirred for 40 min at room temperature. The reaction was then quenched with NH₄Cl (aq.). The aqueous phase was extracted with EA. The organic layer was combined, dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel chromatography (EA/PE) to yield methyl (2S)-1-acryloyl-5-allylpyrrolidine-2-carboxylate as a yellow oil. LC/MS: mass calculated for C₁₂H₁₇NO₃: 223.12, measured: 224.20 [M+H]⁺.

Step 3: Methyl (3S)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

Under N₂, to a solution of methyl (2S)-1-acryloyl-5-allylpyrrolidine-2-carboxylate (7.2 g, 32.25 mmol, 1.0 eq) in DCM (100 mL) was added Grubbs' 2nd catalyst (2.7 g, 3.23 mmol, 0.1 eq). The resulting mixture was heated at 45° C. for 10 h and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (EA/PE) to yield methyl (3S)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as brown oil. LC/MS: mass calculated for C₁₀H₁₃NO₃: 195.09, measured: 196.10 [M+H]⁺.

Step 4: Methyl (3S)-7-hydroxy-5-oxooctahydroindolizine-3-carboxylate

Under N₂, to a solution of CuCl (0.102 g, 1.03 mmol, 0.2 eq) in THF (100 mL) was added BINAP (638 mg, 1.03 mmol, 0.2 eq). The mixture was stirred for 15 min. Then t-BuONa (98 mg, 1.03 mmol, 0.2 eq) was added. 30 min later, 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.6 g, 6.15 mmol, 1.2 eq) was added followed by (3S)-methyl 5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (1.0 g, 5.12 mmol, 1.0 eq). Finally, MeOH (328 mg, 10.25 mmol, 2.0 eq) was added dropwise. The resulting mixture was stirred for 16 h, then cooled to 0° C. H₂O₂ (6 mL, 51.23 mmol, 10.0 eq) was added and the reaction mixture was stirred for another 1 h. The solvent was removed under reduced pressure and the residue was purified through silica gel (DCM/MeOH) to yield methyl (3S)-7-hydroxy-5-oxooctahydroindolizine-3-carboxylate as a brown oil, which was used in the next step without further purification.

Step 5: Methyl (3S)-5,7-dioxooctahydroindolizine-3-carboxylate

To a solution of (3S)-methyl 7-hydroxy-5-oxo-octahydroindolizine-3-carboxylate (1.0 g) in DCM (100 mL) was added pyridinium chlorochromate (2.0 g, 9.38 mmol, 2.0 eq). The resulting mixture was stirred for 16 h. The solvent was removed under reduced pressure and the residue was purified through silica gel (EA/PE) to yield (3S)-methyl 5,7-dioxo-octahydroindolizine-3-carboxylate was afforded as a yellow oil. LC/MS: mass calculated for C₁₀H₁₃NO₄: 211.08, measured: 212.10 [M+H]⁺.

Example C: Methyl (3S)-5,7-dioxooctahydroindolizine-3-carboxylate (Method C)

Step 1: Diethyl (S)-2-((tert-butoxycarbonyl)amino)-5-oxoheptanedioate

Into a 3-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tetrahydrofuran (1.0 L), and LDA (253 mL, 2 M in THF, 1.00 equiv). This was followed by the addition a solution of ethyl acetate (44.5 g, 505.2 mmol, 1.00 equiv) in THF (100 mL) dropwise with stirring at −78° C. The resulting mixture was then stirred for 30 min. To the mixture was added a solution of 1-tert-butyl 2-ethyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate (130 g, 505.2 mmol, 1.00 equiv) in THF (300 mL) with stirring at −78° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of NH₄Cl (aq., 50 mL). The resulting mixture was extracted with dichloromethane (3×1 L) and the organic layers were combined. The combined layer mixture was washed with brine (2×500 mL). The mixture was dried over anhydrous sodium sulfate and concentrated. The resulting residue was applied onto a silica gel column with ethyl acetate to yield diethyl (S)-2-((tert-butoxycarbonyl)amino)-5-oxoheptanedioate as a yellow oil. ¹H NMR: (300 MHz, CDCl₃, ppm) δ 5.21-5.09 (m, 1H), 4.23-4.05 (m, 5H), 3.39 (s, 2H), 2.72-2.56 (m, 2H), 2.20-2.05 (m, 1H), 1.94-1.80 (m, 1H), 1.41 (s, 9H), 1.31-1.20 (m, 6H).

Step 2: Ethyl (S,Z)-5-(2-ethoxy-2-oxoethylidene)pyrrolidine-2-carboxylate

Into a 3-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1,7-diethyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-oxoheptanedioate (105.0 g, 304.0 mmol, 1.00 equiv), and trifluoroacetic acid (59.6 g, 608.0 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 25° C., then was concentrated. The resulting solution was diluted with DCM (100 mL). The pH value of the solution was adjusted to 7 with Na₂CO₃. The resulting solution was extracted with dichloromethane (3×500 mL), the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) to yield ethyl (S,Z)-5-(2-ethoxy-2-oxoethylidene)pyrrolidine-2-carboxylate as a light yellow oil. LC/MS: mass calculated for C₁₁H₁₇NO₄: 227.12, measured: 228.00 [M+H]⁺.

Step 3: Ethyl (2S,5R)-5-(2-ethoxy-2-oxoethyl)pyrrolidine-2-carboxylate

Into a 500 ml round-bottom flask, was placed acetic acid (280 mL), ethyl (2S,5Z)-5-(2-ethoxy-2-oxoethylidene)pyrrolidine-2-carboxylate (35.0 g, 154.0 mmol, 1.00 equiv), and PtO₂ (4.2 g, 18.5 mmol, 0.12 equiv). A H₂ balloon was attached and the mixture was stirred for 3 h at room temperature. The mixture was concentrated and diluted with ethyl acetate (3 L). NaHCO₃ aqueous solution was used to adjust the mixture pH to 7. The resulting solution was extracted with ethyl acetate (3×2 L), dried over anhydrous sodium sulfate and concentrated to yield ethyl (2S,5R) 5-(2-ethoxy-2-oxoethyl)pyrrolidine-2-carboxylate as yellow oil. ¹HNMR (300 MHz, CDCl₃, ppm) δ 4.19 (dq, J=11.5, 7.1 Hz, 4H), 3.87 (dd, J=9.0, 5.5 Hz, 1H), 3.71 (s, 1H), 3.63-3.48 (m, 1H), 2.69-2.49 (m, 2H), 2.23-2.08 (m, 1H), 2.05-1.91 (m, 2H), 1.55-1.36 (m, 1H), 1.29 (dt, J=11.5, 7.1 Hz, 6H).

Step 4: ethyl (2S,5R)-5-(2-ethoxy-2-oxoethyl)-1-(3-ethoxy-3-oxopropanoyl)pyrrolidine-2-carboxylate

Into a 2-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed DCM (700 mL), DIPEA (39.4 g, 305.3 mmol, 2.00 equiv), and ethyl (2S,5R)-5-(2-ethoxy-2-oxoethyl)pyrrolidine-2-carboxylate (35.0 g, 152.6 mmol, 1.00 equiv). This was followed by the addition of a solution of ethyl 3-chloro-3-oxopropanoate (29.9 g, 198.4 mmol, 1.30 equiv) in DCM (50 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was washed with water (2×200 mL). The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20-1:2) to yield ethyl (2S,5R)-5-(2-ethoxy-2-oxoethyl)-1-(3-ethoxy-3-oxopropanoyl)pyrrolidine-2-carboxylate as yellow oil. LC/MS: mass calculated for C₁₆H₂₅NO₇: 343.16, measured: 334.00 [M+H]⁺.

Step 5: Diethyl (3S,8aR)-5,7-dioxooctahydroindolizine-3,6-dicarboxylate

Into a 1-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl alcohol (500 mL), ethyl (2S,5R)-5-(2-ethoxy-2-oxoethyl)-1-(3-ethoxy-3-oxopropanoyl)pyrrolidine-2-carboxylate (38.6 g, 112.4 mmol, 1.00 equiv), and sodium ethoxide (8.0 g, 118.0 mmol, 1.05 equiv). The resulting solution was stirred for 50 min at 60° C. The reaction mixture was cooled with a water/ice bath and concentrated. The mixture was poured into 1N HCl (300 mL). The resulting solution was extracted with ethyl acetate (2×200 mL) acetate, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20-1:3) to yield diethyl (3S,8aR)-5,7-dioxooctahydroindolizine-3,6-dicarboxylate as yellow oil. LC/MS: mass calculated for C₁₄H₁₉NO: 297.12, measured: 298.00 [M+H]⁺.

Step 6: Ethyl (3S,8aR)-5,7-dioxooctahydroindolizine-3-carboxylate

Into a 2-L 3-necked round-bottom flask, was placed 3,6-diethyl (3S,8aR)-5,7-dioxo-hexahydroindolizine-3,6-dicarboxylate (28.0 g, 94.1 mmol, 1.00 equiv), acetic acid (196 mL), H₂O (20 mL). The resulting solution was stirred for 2 h at 110° C. The reaction mixture was cooled with a water/ice bath. The resulting mixture was concentrated to yield ethyl (3S,8aR)-5,7-dioxo-hexahydroindolizine-3-carboxylate as yellow oil.

¹HNMR (300 MHz, CDCl₃, ppm) δ 4.63 (d, J=8.0 Hz, 1H), 4.23 (q, J=7.1 Hz, 2H), 4.08-3.90 (m, 1H), 3.32 (s, 2H), 2.88 (dd, J=16.6, 3.2 Hz, 1H), 2.65-2.54 (m, 1H), 2.41-2.09 (m, 3H), 1.99-1.79 (m, 1H), 1.31 (t, J=7.1 Hz, 3H).

Example D: (3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-1,1-dimethyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

Step 1: 1-(Tert-butyl) 2-methyl (S)-4,4-dimethyl-5-oxopyrrolidine-1,2-dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (20.0 g, 82.20 mmol, 1.0 equiv.) in tetrahydrofuran (300 mL), was added lithium bis(trimethylsilyl)amide (86.0 mL, 86.30 mmol, 1.05 equiv.) drop-wise at −78° C. The reaction mixture was stirred for 1 h at −78° C., then iodomethane (7.7 mL, 123.30 mmol, 1.5 equiv.) was added at −78° C. The reaction was warmed at room temperature and stirred for another 1 h. The reaction was quenched by water (200 mL) and extracted with ethyl acetate (2×200 mL), and the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to yield 1-(tert-butyl) 2-methyl (S)-4,4-dimethyl-5-oxopyrrolidine-1,2-dicarboxylate as a white solid. LC/MS: mass calculated for C₁₃H₂₁NO₅: 271.14, measured: 565.25 [2M+Na]⁺.

Step 2: 1-(Tert-butyl) 2-methyl (2S)-5-methoxy-4,4-dimethylpyrrolidine-1,2-dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl (S)-4,4-dimethyl-5-oxopyrrolidine-1,2-dicarboxylate (10.0 g, 36.86 mmol, 1.0 equiv.) in THF (200 mL), was added lithium triethylborhydride (55.3 mL, 55.3 mmol, 1.5 equiv., 1M in THF) drop-wise at −78° C. The reaction was stirred for 40 min at −78° C., then Na₂CO₃ (50 mL) was added at −78° C. and the mixture was warmed to 0° C., Hydrogen peroxide (10 mL, 30%) was added. The mixture was stirred for 30 min at room temperature. THF was removed under vacuum, and the resulting residue was extracted with ethyl acetate, washed with brine, dried and concentrated under vacuum to yield a colorless oil. The colorless oil was dissolved by methanol (200 mL), and p-toluenesulfonic acid (0.60 g, 3.69 mmol, 0.1 equiv.) was added. The solution was stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated to yield 1-(tert-butyl) 2-methyl (2S)-5-methoxy-4,4-dimethylpyrrolidine-1,2-dicarboxylate (9.3 g, 87.8%) as a colorless oil.

Step 3: 1-(Tert-butyl) 2-methyl (2S)-5-allyl-4,4-dimethylpyrrolidine-1,2-dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl (2S)-5-methoxy-4,4-dimethylpyrrolidine-1,2-dicarboxylate (9.3 g, 32.36 mmol, 1.0 equiv.) in ethoxyethane (200 mL), were added allyltrimethylsilane (22.6 ml, 142.40 mmol, 4.4 equiv.) and boron trifluoride etherate (5.5 g, 38.80 mmol, 1.2 equiv.) at −40° C. The reaction was stirred for 30 min at −40° C., and then warmed to room temperature and stirred for 40 min. The reaction was quenched with Na₂CO₃ and extracted with ethoxyethane. The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc/petroleum ether) to yield 1-(tert-butyl) 2-methyl (2S)-5-allyl-4,4-dimethylpyrrolidine-1,2-dicarboxylate as a colorless oil.

Step 4: Methyl (2S)-5-allyl-4,4-dimethylpyrrolidine-2-carboxylate

To a solution of 1-(tert-butyl) 2-methyl (2S)-5-allyl-4,4-dimethylpyrrolidine-1,2-dicarboxylate (5.2 g, 17.49 mmol, 1.0 equiv.) in dichloromethane (50 mL), was added HCl in 1,4-dioxane (50 mL, 4N). The reaction was stirred for 2 h at room temperature. The resulting solution was concentrated under vacuum to yield methyl (2S)-5-allyl-4,4-dimethylpyrrolidine-2-carboxylate as a white solid, which was used in the next step without further purification.

Step 5: Methyl (2S)-1-acryloyl-5-allyl-4,4-dimethylpyrrolidine-2-carboxylate

To a solution of methyl (2S)-5-allyl-4,4-dimethylpyrrolidine-2-carboxylate (3.2 g, 0.96 mmol, 1.0 equiv.) in tetrahydrofuran (50 mL), was added triethylamine (11.3 mL, 81.1 mmol, 5.0 equiv.). The reaction mixture was stirred at −78° C. and then acryloyl chloride (1.5 mL, 17.80 mmol, 1.1 equiv.) was added dropwise under N₂. The reaction was stirred for 2 h at room temperature. The reaction was quenched by water and extracted with ethyl acetate, and the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3) to yield methyl (2S)-1-acryloyl-5-allyl-4,4-dimethylpyrrolidine-2-carboxylate as a yellow oil. LC/MS: mass calculated for C₁₄H₂₁NO₃: 251.15, measured: 252.20 [M+H]⁺.

Step 6: Methyl (3S)-1,1-dimethyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of methyl (2S)-1-acryloyl-5-allyl-4,4-dimethylpyrrolidine-2-carboxylate (3.6 g, 14.30 mmol, 1.0 equiv.) in dichloromethane (100 mL), was added Grubbs catalyst 2nd generation (609 mg, 0.70 mmol, 0.05 equiv.). The reaction mixture was stirred overnight at 45° C. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3) to yield methyl (3S)-1,1-dimethyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a brown oil. LC/MS: mass calculated for C₁₂H₁₇NO₃: 223.12, measured: 224.20 [M+H]⁺.

Step 7: Methyl (3S)-7-hydroxy-1,1-dimethyl-5-oxooctahydroindolizine-3-carboxylate

A flask was charged with copper (I) chloride (0.24 g, 2.42 mmol, 0.2 equiv.) and BINAP (1.5 g, 2.42 mmol, 0.2 equiv.) under nitrogen. Freshly degassed (freeze-pump-thaw) THF (40 mL) was added and the yellow reaction mixture was stirred for 15 min. Then, sodium tert-butoxide (0.23 g, 2.42 mmol, 0.2 equiv.) was added in one portion and stirring was continued for 30 min. Bis(pinacolato)diboron (3.7 g, 14.50 mmol, 1.2 equiv.) was added and the reaction mixture was stirred for 10 min, then a solution of methyl (3S)-1,1-dimethyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (2.7 g, 12.10 mmol, 1.00 equiv.) in THF (10 mL) was added drop-wise, followed by the addition of MeOH (0.78 g, 24.20 mmol, 2 equiv.). The mixture was stirred for 16 h, then 30% hydrogen peroxide (13.7 mL, 120.9 mmol, 10 eq) was added at 0° C. The resulting solution was stirred 1 h at room temperature. The mixture was concentrated under vacuum. The residue was purified by C18 (0-40% H₂O/CH₃CN) to yield methyl (3S)-7-hydroxy-1,1-dimethyl-5-oxooctahydroindolizine-3-carboxylate as a colorless oil. LC/MS: mass calculated for C₁₂H₁₉NO₄: 241.13, measured: 242.20 [M+H]⁺.

Step 8: Methyl (3S)-1,1-dimethyl-5,7-dioxooctahydroindolizine-3-carboxylate

To a solution of methyl (3S)-7-hydroxy-1,1-dimethyl-5-oxooctahydroindolizine-3-carboxylate (2.2 g, 9.12 mmol, 1.0 equiv.) in dichloromethane (100 mL), was added pyridinium chlorochromate (3.9 g, 18.20 mmol, 2.0 equiv.). The reaction mixture was stirred overnight at room temperature. The precipitate was filtered off, washed with dichloromethane. The filtrate was concentrated and the residue was applied onto a silica gel column with DCM/MeOH (10:1) to yield methyl (3S)-1,1-dimethyl-5,7-dioxooctahydroindolizine-3-carboxylate as a brown oil. LC/MS: mass calculated for C₁₂H₁₇NO₄: 239.12, measured: 240.20 [M+H]⁺.

Step 9: Methyl (3S)-1,1-dimethyl-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of methyl (3S)-1,1-dimethyl-5,7-dioxooctahydroindolizine-3-carboxylate (2.2 g, 9.20 mmol, 1.0 equiv.) in dichloromethane (50 mL), were added triethylamine (1.9 g, 18.40 mmol, 2.0 equiv.) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (3.9 g, 11.0 mmol, 1.2 equiv.). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated. The residue was purified by silica gel chromatography (0-80% EA/PE) to yield methyl (3S)-1,1-dimethyl-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow oil. LC/MS: mass calculated for C₁₃H₁₆F₃NO₆S: 371.07, measured: 372.10 [M+H]⁺.

Step 10: Methyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1,1-dimethyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of methyl (3S)-1,1-dimethyl-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (2.0 g, 5.40 mmol, 1.0 equiv.), (6-amino-3-chloro-2-fluorophenyl) boronic acid (1.2 g, 6.50 mmol, 1.2 equiv.) and potassium carbonate (1.5 g, 10.77 mmol 2.0 equiv.) in 1,4-dioxane/H₂O (50 mL, 10/1), was added [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (197 mg, 0.27 mmol, 0.05 equiv.). The reaction mixture was stirred for 2 h at 80° C. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography (0-100% PE/EA) to yield methyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1,1-dimethyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a brown solid. LC/MS: mass calculated for C₁₈H₂₀ClFN₂O₃: 366.11, measured: 367.05 [M+H]⁺.

Step 11: (3S)-7-(6-Amino-3-chloro-2-fluorophenyl)-1,1-dimethyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

To a solution of methyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1,1-dimethyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (1.8 g, 4.90 mmol, 1.0 equiv.) in THF/H₂O/MeOH (20 mL, 3/1/1), was added lithium hydroxide (0.98 g, 24.5 mmol, 5.0 equiv.). The reaction mixture was stirred for 1 h at room temperature, adjusted to pH 4 with HCl, then extracted with ethyl acetate and washed with brine, dried and concentrated under vacuum to yield (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1,1-dimethyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid as a brown solid. LC/MS: mass calculated for C₁₇H₁₈ClFN₂O₃: 352.10, measured: 353.15 [M+H]⁺.

Step 12: (3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-1,1-dimethyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1,1-dimethyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (300 mg, 0.85 mmol, 1.0 equiv.) in acetic acid (5 mL), were added azidotrimethylsilane (0.56 mL, 4.25 mmol, 5.0 equiv) and trimethoxymethane (0.46 mL, 4.25 mmol, 5.0 equiv.).

The reaction mixture was stirred overnight at room temperature and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc/petroleum ether) to yield (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-1,1-dimethyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid as a brown solid. LC/MS: mass calculated for C₁₈H₁₇ClFN₅O₃: 405.10, measured: 406.20 [M+H]⁺.

Example E: (1S,3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-1-methyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

Step 1: 1-(Tert-butyl) 2-methyl (S,E)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (20.0 g, 82.22 mmol, 1.0 equiv.) in 1,2-dimethoxyethane (100 mL), was added 1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (21.49 g, 123.33 mmol, 1.5 equiv.). The reaction mixture was stirred overnight at 70° C.

The residue was applied onto a silica gel column with ethyl acetate/DCM (2:3) to yield 1-(tert-butyl) 2-methyl (S,E)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylate as a white solid. ¹H NMR (300 MHz, Chloroform-d) δ 7.15 (t, J=1.7 Hz, 1H), 4.57 (dd, J=10.7, 3.7 Hz, 1H), 3.77 (s, 3H), 3.19-3.34 (m, 1H), 3.03 (s, 6H), 2.91 (ddd, J=14.7, 4.1, 1.5 Hz, 1H), 1.51 (s, 9H).

Step 2: 1-(Tert-butyl) 2-methyl (2S,4S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl (S,E)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylate (10.0 g, 33.50 mmol, 1.0 equiv0) in isopropanol (1000 mL) was added Pd/C (2.0 g, 10%). The resulting mixture was stirred overnight at room temperature under an atmosphere of hydrogen. The solid was filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (0-45%) to yield of 1-(tert-butyl) 2-methyl (2S,4S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate as a white solid. LC/MS: mass calculated for C₁₂H₁₉NO₅: 257.13, measured: 537.25 [2M+Na]⁺.

Step 3: 1-(Tert-butyl) 2-methyl (2S,4S)-5-methoxy-4-methylpyrrolidine-1,2-dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl (2S,4S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate (15.0 g, 58.30 mmol, 1.0 equiv.) in THF (300 mL), was added lithium triethylborhydride (87.5 mL, 87.50 mmol, 1.5 equiv., 1M in THF) drop-wise at −78° C. The reaction mixture was stirred for 40 min at −78° C., then Na₂CO₃ (100 mL) was added at −78° C. and the mixture was warmed to 0° C. Hydrogen peroxide (8 mL, 30%) was added. The mixture was stirred for 30 min at room temperature. THF was removed under vacuum, and the resulting residue was extracted with ethyl acetate, washed with brine, dried and concentrated under vacuum to yield a colorless oil. The colorless oil was dissolved by methanol (300 mL), and then p-toluenesulfonic acid (1.0 g, 5.83 mmol, 0.1 equiv.) was added. The resulting solution was stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated to yield 1-(tert-butyl) 2-methyl (2S,4S)-5-methoxy-4-methylpyrrolidine-1,2-dicarboxylate as a yellow oil.

Step 4: 1-(Tert-butyl) 2-methyl (2S,4S)-5-allyl-4-methylpyrrolidine-1,2-dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl (2S,4S)-5-methoxy-4-methylpyrrolidine-1,2-dicarboxylate (13.0 g, 47.60 mmol, 1.0 equiv.) in ethoxyethane (200 mL), were added allyltrimethylsilane (33.3 ml, 209.30 mmol, 4.4 equiv.) and boron trifluoride etherate (8.1 g, 57.10 mmol, 1.2 equiv.) at −40° C. The reaction mixture was stirred for 30 min at −40° C., and then warmed to room temperature and stirred for 40 min. The reaction was quenched with Na₂CO₃ and extracted with ethoxyethane. The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc/petroleum ether) to yield 1-(tert-butyl) 2-methyl (2S,4S)-5-allyl-4-methylpyrrolidine-1,2-dicarboxylate as a yellow oil. LC/MS: mass calculated for C₁₅H₂₅NO₄: 283.18, measured: 306.10 [M+Na]⁺.

Step 5: Methyl (2S,4S)-5-allyl-4-methylpyrrolidine-2-carboxylate

To a solution of 1-(tert-butyl) 2-methyl (2S,4S)-5-allyl-4-methylpyrrolidine-1,2-dicarboxylate (9.6 g, 33.90 mmol, 1.0 equiv.) in dichloromethane (100 mL), was added HCl in 1,4-dioxane (100 mL, 4 N). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was then concentrated under vacuum to yield methyl (2S,4S)-5-allyl-4-methylpyrrolidine-2-carboxylate as a white solid. LC/MS: mass calculated for C₁₀H₁₇NO₂: 183.13, measured: 184.05 [M+H]⁺.

Step 6: Methyl (2S,4S)-1-acryloyl-5-allyl-4-methylpyrrolidine-2-carboxylate

To a solution of methyl (2S,4S)-5-allyl-4-methylpyrrolidine-2-carboxylate (3.9 g, 21.10 mmol, 1.0 equiv.) in tetrahydrofuran (50 mL), was added triethylamine (14.6 mL, 105.30 mmol, 5.0 equiv.). The reaction mixture was stirred for −78° C., and acryloyl chloride (1.9 mL, 23.20 mmol, 1.1 equiv.) was added dropwise under N₂. The reaction mixture was stirred for 2 h at room temperature. The reaction was quenched by water (50 mL) and extracted with ethyl acetate (2×50 mL), the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3) to yield methyl (2S,4S)-1-acryloyl-5-allyl-4-methylpyrrolidine-2-carboxylate as a yellow oil. LC/MS: mass calculated for C₁₂H₁₅N₂O₃: 237.14, measured: 238.10 [M+H]⁺.

Step 7: Methyl (1S,3S)-1-methyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of methyl (2S,4S)-1-acryloyl-5-allyl-4-methylpyrrolidine-2-carboxylate (3.0 g, 12.64 mmol, 1.0 equiv.) in dichloromethane (50 mL), was added Grubbs catalyst 2nd generation (538 mg, 0.63 mmol, 0.05 equiv.). The reaction mixture was stirred overnight at 45° C. then concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3) to yield methyl (3S)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a brown oil. LC/MS: mass calculated for C₁₁H₁₅NO₃: 209.11, measured: 210.10 [M+H]⁺.

Step 8: Methyl (1S,3S)-7-hydroxy-1-methyl-5-oxooctahydroindolizine-3-carboxylate

A flask was charged with copper (I) chloride (242 mg, 2.40 mmol, 0.2 equiv.) and BINAP (1.5 g, 2.40 mmol, 0.2 equiv.) under nitrogen. Freshly degassed (freeze-pump-thaw) THF (40 mL) was added and the yellow reaction mixture was stirred for 15 min. Then, sodium tert-butoxide (235 mg, 2.40 mmol, 0.2 equiv.) was added in one portion and stirring was continued for 30 min. Bis(pinacolato)diboron (3.7 g, 14.70 mmol, 1.2 equiv.) was added. The reaction mixture was stirred for 10 min, then a solution of methyl (1S,3S)-1-methyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (2.6 g, 12.24 mmol, 1.0 equiv.) in THF (10 mL) was added drop-wise, followed by addition of MeOH (784 mg, 24.50 mmol, 2.0 equiv.). The reaction mixture was stirred for 16 h. To the mixture was then added 30% hydrogen peroxide (13.9 g, 122.30 mmol, 10.0 equiv.) at 0° C. The resulting solution was stirred 1 h at room temperature. The mixture was concentrated under vacuum. The resulting residue was purified by C18 (0-40% H₂O/CH₃CN) to yield methyl (1S,3S)-7-hydroxy-1-methyl-5-oxooctahydroindolizine-3-carboxylate as a colorless oil. LC/MS: mass calculated for C₁₁H₁₇NO₄: 227.12, measured: 228.10 [M+H]⁺.

Step 9: Methyl (1S,3S)-1-methyl-5,7-dioxooctahydroindolizine-3-carboxylate

To a solution of methyl (1 S,3S)-7-hydroxy-1-methyl-5-oxooctahydroindolizine-3-carboxylate (2.6 g, 11.44 mmol, 1.0 equiv.) in dichloromethane (250 mL), was added pyridinium chlorochromate (4.9 g, 22.88 mmol, 2.0 equiv.). The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was applied onto a silica gel column with DCM/MeOH (10:1) to yield methyl (1S,3S)-1-methyl-5,7-dioxooctahydroindolizine-3-carboxylate as a yellow oil. LC/MS: mass calculated for C₁₁H₁₅NO₄: 225.10, measured: 226.05 [M+H]⁺.

Step 10: Methyl (1S,3S)-1-methyl-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of methyl (1S,3S)-1-methyl-5,7-dioxooctahydroindolizine-3-carboxylate (1.3 g, 5.80 mmol, 1.0 equiv.) in dichloromethane (30 mL), were added triethylamine (1.2 g, 11.50 mmol, 2.0 equiv.) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.5 g, 6.90 mmol, 1.2 equiv.).

The reaction mixture was stirred overnight at room temperature. The mixture was concentrated. The residue was purified by silica gel chromatography (0-40% EA/PE) to yield methyl (1S,3S)-1-methyl-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow oil. LC/MS: mass calculated for C₁₂H₁₄F₃NO₆S: 357.05, measured: 358.00 [M+H]⁺.

Step 11: Methyl (1 S,3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1-methyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of methyl (1S,3S)-1-methyl-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (1.5 g, 4.20 mmol, 1.0 equiv.), (6-amino-3-chloro-2-fluorophenyl) boronic acid (0.95 g, 5.00 mmol, 1.2 equiv.) and potassium carbonate (1.2 g, 8.40 mmol 2.0 equiv.) in 1,4-dioxane/H₂O (20 mL, 10/1), was added [1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (154 mg, 0.21 mmol, 0.1 equiv.). The reaction mixture was stirred for 2 h at 80° C. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography (0-100% PE/EA) to yield methyl (1S,3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1-methyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C₁₇H₁₈ClFN₂O₃: 352.10, measured: 353.10 [M+H]⁺.

Step 12: (1S,3S)-7-(6-Amino-3-chloro-2-fluorophenyl)-1-methyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

To a solution of methyl (1S,3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1-methyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (1.3 g, 3.69 mmol, 1.0 equiv.) in THF/H₂O/MeOH (15 mL, 3/1/1), was added lithium hydroxide (737 mg, 18.40 mmol, 5.0 equiv.). The reaction mixture was stirred for 1 h at room temperature, adjusted to pH 4 with 1N HCl, then extracted with ethyl acetate and washed with brine, dried and concentrated under vacuum to yield (1S,3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1-methyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid as a yellow solid. LC/MS: mass calculated for C₁₆H₁₆ClFN₂O₃: 338.08, measured: 339.05 [M+H]⁺.

Step 13: (1S,3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-1-methyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

To a solution of (1S,3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1-methyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (500 mg, 1.50 mmol, 1.0 equiv) in acetic acid (10 mL), were added azidotrimethylsilane (0.97 mL, 7.38 mmol, 5.0 equiv.) and trimethoxymethane (0.8 mL, 7.38 mmol, 5.0 equiv.). The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc/petroleum ether) to yield (1S,3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-1-methyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid as a brown solid. LC/MS: mass calculated for C₁₇H₁ClFN₅O₃: 391.08, measured: 392.15 [M+H]⁺.

Example F: (1R,3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-1-methoxy-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

Step 1: 1-(Tert-butyl) 2-methyl (2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (10.0 g, 40.77 mmol, 1.0 equiv.) in N,N-dimethylformamide (150 mL), was added sodium hydride (1.8 g, 44.85 mmol, 1.1 equiv.) at 0° C. The reaction mixture was stirred for 30 min at 0° C. Iodomethane (11.6 g, 81. mmol, 2.0 equiv.) was then added and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with water extracted with ethoxyethane. The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc/petroleum ether) to yield 1-(tert-butyl) 2-methyl 4-methoxypyrrolidine-1,2-dicarboxylate as a yellow oil. LC/MS: mass calculated for C₁₂H₂₁NO₅: 259.14, measured: 160.20 [M-Boc]⁺.

Step 2: 1-(Tert-butyl) 2-methyl (2S,4R)-4-methoxy-5-oxopyrrolidine-1,2-dicarboxylate

To a solution of sodium periodate (20.6 g, 96.41 mmol, 2.5 equiv.) in H₂O (160 mL) was added ruthenium trichloride (1.6 g, 7.71 mmol, 0.2 equiv.) under nitrogen. The resulting solution was stirred for 5 minutes, followed by addition of 1-(tert-butyl) 2-methyl 4-methoxypyrrolidine-1,2-dicarboxylate (10.0 g, 38.57 mmol, 1.0 equiv.) in EtOAc (88 mL) in one portion. The mixture was then stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate (2×100 mL) and washed with Na₂SO₃ solution (100 mL), the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3) to yield 1-(tert-butyl) 2-methyl (2S,4R)-4-methoxy-5-oxopyrrolidine-1,2-dicarboxylate as a yellow oil. LC/MS: mass calculated for C₁₂H₁₉NO₆: 273.12, measured: 569.30 [2M+Na]⁺.

Step 3: 1-(Tert-butyl) 2-methyl (2S,4R)-4,5-dimethoxypyrrolidine-1,2-dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl (2S,4R)-4-methoxy-5-oxopyrrolidine-1,2-dicarboxylate (6.5 g, 23.79 mmol, 1.0 equiv.) in THF (100 mL), was added lithium triethylborhydride (35.7 mL, 35.7 mmol, 1.5 equiv., 1M in THF) dropwise at −78° C. The reaction mixture was stirred for 40 min at −78° C., then NaHCO₃ (40 mL) was added at −78° C., and the mixture was warmed to 0° C. Hydrogen peroxide (4 mL, 30%) was added. The mixture was stirred for 30 min at room temperature. THF was removed under vacuum, and extracted with diethyl ether, washed with brine, dried and concentrated under vacuum to yield a colorless oil. The colorless oil was dissolved by methanol (100 mL), and then p-toluenesulfonic acid (410 mg, 2.38 mmol, 0.1 equiv.) was added. The resulting solution was stirred overnight at room temperature. The reaction was quenched with NaHCO₃ and extracted with diethyl ether. The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated to yield 1-(tert-butyl) 2-methyl (2S,4R)-4,5-dimethoxypyrrolidine-1,2-dicarboxylate as a colorless oil.

Step 4: 1-(Tert-butyl) 2-methyl (2S,4R)-5-allyl-4-methoxypyrrolidine-1,2-dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl (2S,4R)-4,5-dimethoxypyrrolidine-1,2-dicarboxylate (5.0 g, 17.28 mmol, 1.0 equiv.) in diethyl ether (100 mL), were added allyltrimethylsilane (12.1 ml, 76.04 mmol, 4.4 equiv.) and boron trifluoride etherate (2.9 g, 20.74 mmol, 1.2 equiv.) at −40° C. The reaction mixture was stirred for 30 min at −40° C., and then warmed to room temperature and stirred for 40 min. The reaction was quenched with Na₂CO₃ and extracted with ethoxyethane. The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc/petroleum ether) to yield 1-(tert-butyl) 2-methyl (2S)-5-allylpyrrolidine-1,2-dicarboxylate as a yellow oil.

Step 5: Methyl (2S,4R)-5-allyl-4-methoxypyrrolidine-2-carboxylate

To a solution of 1-(tert-butyl) 2-ethyl 5-allyl-3-methylpyrrolidine-1,2-dicarboxylate (12.6 g, 42.09 mmol, 1.0 equiv.) in dichloromethane (200 mL), was added HCl in 1,4-dioxane (120 mL, 4N). The reaction mixture was stirred for 2 h at room temperature. The resulting solution was concentrated under vacuum to yield methyl (2S,4R)-5-allyl-4-methoxypyrrolidine-2-carboxylate as a white solid. LC/MS: mass calculated for C₁₀H₁₇NO₃: 199.12, measured: 200.05 [M+H]⁺.

Step 6: Methyl (2S,4R)-1-acryloyl-5-allyl-4-methoxypyrrolidine-2-carboxylate

To a solution of methyl (2S,4R)-5-allyl-4-methoxypyrrolidine-2-carboxylate (9.6 g, 40.73 mmol, 1.0 equiv.) in tetrahydrofuran (200 mL), was added triethylamine (28.3 mL, 203.64 mmol, 5.0 equiv.). The reaction mixture was stirred for −78° C., and then acryloyl chloride (3.6 mL, 44.80 mmol, 1.1 equiv.) was added drop-wise under N₂. The reaction mixture was stirred for 2 h at room temperature. The reaction was quenched by water (100 mL) and extracted with ethyl acetate (2×100 mL), and the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3) to yield methyl (2S,4R)-1-acryloyl-5-allyl-4-methoxypyrrolidine-2-carboxylate as a yellow oil. LC/MS: mass calculated for C₁₃H₁₉NO₄: 253.13, measured: 254.10 [M+H]⁺.

Step 7: Methyl (1R,3S)-1-methoxy-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of methyl (2S,4R)-1-acryloyl-5-allyl-4-methoxypyrrolidine-2-carboxylate (8.5 g, 33.56 mmol, 1.0 equiv.) in dichloromethane (200 mL), was added Grubbs catalyst 2nd generation (1.4 g, 1.68 mmol, 0.05 equiv.). The reaction mixture was stirred overnight at 45° C. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3) to yield of methyl (1R,3S)-1-methoxy-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a brown oil. LC/MS: mass calculated for C₁₁H₁₅NO₄: 223.12, measured: 226.10 [M+H]⁺.

Step 8: Methyl (1R,3S)-7-hydroxy-1-methoxy-5-oxooctahydroindolizine-3-carboxylate

A flask was charged with copper(I) chloride (264 mg, 2.66 mmol, 0.2 equiv.) and BINAP (1.7 g, 2.66 mmol, 0.2 equiv.) under nitrogen. Freshly degassed (freeze-pump-thaw) THF (200 mL) was added and the yellow reaction mixture was stirred for 15 min. Then sodium tert-butoxide (256 mg, 2.66 mmol, 0.2 equiv.) was added in one portion and stirring was continued for 30 min. Bis(pinacolato)diboron (4.1 g, 15.98 mmol, 1.2 equiv.) was added and the reaction mixture was stirred for 10 min. Then, a solution of methyl (1R,3S)-1-methoxy-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (3.0 g, 13.32 mmol, 1.0 equiv.) in THF (40 mL) was added drop-wise, followed by addition of MeOH (0.85 g, 26.64 mmol, 2.0 equiv.). The mixture was stirred for 16 h, then 30% hydrogen peroxide (15.1 mL, 133.19 mmol, 10.0 equiv.) was added at 0° C. The resulting solution was stirred overnight at room temperature. The mixture was concentrated under vacuum. The residue was purified by silica gel column (0-10% MeOH/DCM) to yield methyl (1R,3S)-7-hydroxy-1-methoxy-5-oxooctahydroindolizine-3-carboxylate as a yellow oil and methyl (1R,3S)-1-methoxy-5-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)octahydroindolizine-3-carboxylate as a brown solid. LC/MS: mass calculated for C₁₁H₁₇NO₅: 243.11, measured: 244.10 [M+H]⁺, mass calculated for C₁₇H₂₈BNO₆: 353.20, measured: 354.20 [M+H]⁺.

To a solution of the methyl (1R,3S)-1-methoxy-5-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)octahydroindolizine-3-carboxylate (3.8 g, 10.76 mmol, 1.0 equiv.) in THF/H₂O (40 mL, 3/1), was added sodium perborate trihydrate (4.4 g, 53.79 mmol, 5.0 equiv.). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum. The residue was purified by silica gel column (0-10% MeOH/DCM) to yield additional methyl (1R,3S)-7-hydroxy-1-methoxy-5-oxooctahydroindolizine-3-carboxylate as a yellow oil. LC/MS: mass calculated for C₁₁H₁₇NO₅: 243.11, measured: 244.20 [M+H]⁺.

Step 9: Methyl (1R,3S)-1-methoxy-5,7-dioxooctahydroindolizine-3-carboxylate

To a solution of methyl (1R,3S)-7-hydroxy-1-methoxy-5-oxooctahydroindolizine-3-carboxylate (3.4 g, 13.98 mmol, 1.0 equiv.) in dichloromethane (150 mL), was added pyridinium chlorochromate (6.0 g, 27.95 mmol, 2.0 equiv.). The reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column (0-10% MeOH/DCM) to yield methyl (1R,3S)-1-methoxy-5,7-dioxooctahydroindolizine-3-carboxylate as a brown solid. LC/MS: mass calculated for C₁₁H₁₅NO₅: 241.10, measured: 242.20 [M+H]⁺.

Step 10: Methyl (1R,3S)-1-methoxy-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of methyl (1R,3S)-1-methoxy-5,7-dioxooctahydroindolizine-3-carboxylate (2.3 g, 9.53 mmol, 1.0 equiv.) in dichloromethane (30 mL), were added triethylamine (1.9 g, 19.07 mmol, 2.0 equiv.) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (4.1 g, 11.44 mmol, 1.2 equiv.). The reaction mixture was stirred overnight at room temperature. The resulting mixture was then concentrated. The residue was purified by silica gel chromatography (0-60% EA/PE) to yield methyl (1R,3S)-1-methoxy-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow oil. LC/MS: mass calculated for C₁₂H₁₄F₃NO₇S: 373.04, measured: 374.05 [M+H]⁺.

Step 11: Methyl (1R,3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1-methoxy-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of methyl (1R,3S)-1-methoxy-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (3.0 g, 8.04 mmol, 1.0 equiv.), (6-amino-3-chloro-2-fluorophenyl)boronic acid (1.8 g, 9.64 mmol, 1.2 equiv.) and potassium carbonate (2.2 g, 16.07 mmol, 2.0 equiv.) in 1,4-dioxane/H₂O (50 mL, 10/1), was added [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (294 mg, 0.40 mmol, 0.1 equiv.). The reaction mixture was stirred for 2 h at 80° C. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography (0-100% PE/EA) to yield methyl (1R,3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1-methoxy-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a brown solid. LC/MS: mass calculated for C₁₇H₁₈ClFN₂O₄: 368.09, measured: 369.10 [M+H]⁺.

Step 12: (1R,3S)-7-(6-Amino-3-chloro-2-fluorophenyl)-1-methoxy-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

To a solution of methyl (1R,3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1-methoxy-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (2.2 g, 5.97 mmol, 1.0 equiv.) in THF/H₂O/MeOH (50 mL, 3/1/1), was added lithium hydroxide (1.2 g, 29.83 mmol, 5.0 equiv.). The reaction mixture was stirred for 1 h at room temperature, adjusted to pH 4 with 1N HCl, then extracted with ethyl acetate and washed with brine, dried and concentrated under vacuum to yield (1R,3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1-methoxy-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid as a brown solid.

Step 13: (1R,3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-1-methoxy-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

To a mixture of methyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1-methoxy-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (1.0 g, 2.82 mmol, 1.0 equiv.) in acetic acid (15 mL) was added trimethoxymethane (3.0 g, 28.19 mmol, 10.0 equiv.) and azidotrimethylsilane (3.2 g, 28.19 mmol, 10.0 equiv.). The reaction mixture was stirred at room temperature overnight. The resulting mixture was washed with water (3×20 mL), dried over Na₂SO₄, and concentrated. The residue was applied onto a silica gel column (MeOH/DCM: 1/10) to yield methyl (3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as yellow oil. LC/MS: mass calculated for C₁₇H₁₁ClFN₅O₄: 407.08, measured: 408.10 [M+H]⁺.

Example G: (3S)-7-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

Step 1: Methyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a mixture of methyl 5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (5.0 g, 14.57 mmol, 1.0 equiv.) and (6-amino-3-chloro-2-fluorophenyl)boronic acid (5.5 g, 29.13 mmol, 2.0 equiv.) in 1,4-dioxane (50 mL) and water (10 mL) was added potassium phosphate (7.7 g, 36.41 mmol, 2.5 equiv.) and Pd(dppf)Cl₂ (1.1 g, 1.46 mmol, 0.1 equiv.). The flask was evacuated and flushed three times with nitrogen. The resulting solution was stirred at 100° C. for 1 h under N₂. To the resulting solution was added water, and the mixture was extracted with EA twice. The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by silica gel chromatography (0→80% EA/PE) to yield methyl 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C₁₆H₁₆ClFN₂O₃: 338.08, measured (ES, m/z): 339.10 [M+H]⁺.

Step 2: Methyl (3S)-7-(6-azido-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a mixture of methyl 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (3.4 g, 10.04 mmol, 1.0 equiv.) and azidotrimethylsilane (2.6 mL, 20.07 mmol, 2.0 equiv.) in acetonitrile (35 mL) was added tert-butyl nitrite (2.4 mL, 20.07 mmol, 2.0 equiv.) at 0° C. The resulting solution was stirred at room temperature for 1 h. To the resulting mixture was added water, and the mixture was then extracted with EA twice. The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by silica gel chromatography (0→80% EA/PE) to yield methyl 7-(6-azido-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C₁₆H₁₄ClFN₄O₃: 364.07, measured (ES, m/z): 365.10 [M+H]⁺.

Step 3: Methyl (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a mixture of methyl 7-(6-azido-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (2.9 g, 7.95 mmol, 1.0 equiv.) and 4,4,4-trifluorobut-2-ynoic acid (5.5 g, 39.75 mmol, 5.0 equiv.) in acetonitrile (30 mL) was added cuprous oxide (455 mg, 3.18 mmol, 0.4 equiv.). The flask was evacuated and flushed three times with nitrogen. The resulting solution was stirred at 80° C. for 2 h under N₂. The resulting solution was then concentrated under vacuum and purified by silica gel chromatography (0→60% EA/PE) to yield methyl 7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a white solid. LC/MS: mass calculated for C₁₉H₁₅ClF₄N₄O₃: 458.08, measured (ES, m/z): 459.05 [M+H]⁺.

Step 4: (3S)-7-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

To a mixture of methyl 7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (2.8 g, 6.10 mmol, 1.0 equiv.) in acetonitrile (30 mL) and water (0.2 mL) was added triethylamine (5.0 mL, 36.62 mmol, 6.0 equiv.) and lithium bromide (1.6 g, 18.31 mmol, 3.0 equiv.). The resulting solution was stirred at 60° C. for 18 h. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase chromatography on C18 (330 g, ACN/H₂O (0.05% CF₃COOH): 0→30%) to yield 7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid as a yellow solid. LC/MS: mass calculated for C₁₈H₁₃ClF₄N₄O₃: 444.06, measured (ES, m/z): 445.15 [M+H]⁺.

SYNTHESIS EXAMPLES: COMPOUNDS OF FORMULA (I) Example 1: (3S*)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-((R*)-1-hydroxyethyl)quinoxalin-6-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

Step 1: 2-(1-ethoxyvinyl)-6-nitroquinoxaline

To a solution of 2-chloro-6-nitroquinoxaline (2.0 g, 9.54 mmol, 1.0 equiv) in 1,4-dioxane (30 mL) under N₂ was added tributyl(1-ethoxyethenyl)stannane (5.2 g, 14.40 mmol, 1.5 equiv) and Pd(PPh₃)₄ (551 mg, 0.48 mmol, 0.05 equiv). The resulting mixture was stirred for 3 h at 100° C. The reaction mixture was concentrated to yield 2-(1-ethoxyvinyl)-6-nitroquinoxaline as a yellow solid, which was used in the next step without further purification. LC/MS: mass calculated for C₁₂H₁₁N₃O₃: 245.08, measured: 246.05 [M+H]⁺.

Step 2: 1-(6-nitroquinoxalin-2-yl)ethan-1-one

To a solution of 2-(1-ethoxyvinyl)-6-nitroquinoxaline (2.0 g) in THF (20 ml) at 0° C. was added 6N HCl (4 ml). The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was diluted with water (100 mL). The resulting mixture was extracted with EA (3×100 ml). The organic layers were combined, dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel chromatography (0-60% EA/PE) to yield 1-(6-nitroquinoxalin-2-yl)ethan-1-one as a yellow solid. LC/MS: mass calculated for C₁₀H₇N₃O₃: 217.05, measured: 218.20[M+H]⁺

Step 3: 1-(6-nitroquinoxalin-2-yl)ethan-1-ol

To a solution of 1-(6-nitroquinoxalin-2-yl)ethan-1-one (620 mg, 2.86 mmol, 1 equiv) in MeOH (10 ml) at −10° C. was added NaBH₄ (108 mg, 2.86 mmol, 1 equiv). The mixture was stirred for 20 min at −10° C. The reaction was quenched with H₂O (50 ml). The resulting mixture was extracted with EA (3×50 ml). The organic layers were combined, dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% EA/PE) to yield 1-(6-nitroquinoxalin-2-yl)ethan-1-ol as a yellow solid. LC/MS: mass calculated for C₁₀H₉N₃O₃: 219.06, measured: 220.25 [M+H]⁺

Step 4: 2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-nitroquinoxaline

To a solution of 1-(6-nitroquinoxalin-2-yl)ethan-1-ol (529 mg, 2.41 mmol, 1.0 equiv) and 2,6-dimethylpyridine (388 mg, 3.62 mmol, 1.5 equiv) in DCM (8 ml) at 0° C. was added TBSOTf (766 mg, 2.90 mmol, 1.2 equiv). The reaction mixture was stirred for 3 h at room temperature. The reaction was quenched with H₂O (50 ml). The resulting mixture was extracted with DCM (3×50 ml). The organic layers were combined, dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% EA/PE) to yield 2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-nitroquinoxaline as a yellow solid. LC/MS: mass calculated for C₁₆H₂₃N₃O₃Si: 333.15, measured: 334.30 [M+H]⁺.

Step 5: 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-7-amine

To a solution of 2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-nitroquinoxaline (450 mg, 1.35 mmol, 1.0 equiv.) in anhydrous EA (10 ml) at room temperature was added Pd/C (143 mg, 0.14 mmol, 10% wet, 0.1 equiv.). Hydrogen was then introduced to the mixture. The resulting solution was stirred for 1 h at room temperature. The solids were filtered out. The resulting mixture was concentrated and dried under vacuum to yield 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-7-amine as a yellow solid, which was used directly in the next step without further purifications. LC/MS: mass calculated for C₁₆H₂₅N₃OSi: 303.18, measured: 304.30 [M+H]⁺

Step 6: (3*S)—N-(2-(1-((tert-butyldimethylsilyl)oxy)ethyl)quinoxalin-6-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

To a solution of (3*S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (300 mg, 0.79 mmol, 1.0 equiv) in pyridine (10 ml) was added 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-7-amine (362 mg, 1.19 mmol, 1.5 equiv) and EDCl (304 mg, 1.59 mmol, 2.0 equiv) under N₂. The reaction mixture was overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse C18 column (10-60% H₂O (0.05% TFA)/ACN) to yield (3*S)—N-(2-(1-((tert-butyldimethylsilyl)oxy)ethyl)quinoxalin-6-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as a yellow solid. LC/MS: mass calculated for C₃₂H₃₆ClFN₈O₃Si: 662.24, measured: 663.40 [M+H]⁺.

Step 7: (3*S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-((*R)-1-hydroxyethyl)quinoxalin-6-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

To a solution of (3*S)—N-(2-((S)-1-((tert-butyldimethylsilyl)oxy)ethyl)quinoxalin-6-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide (330 mg, 0.50 mmol, 1.0 equiv.) in THF (10 ml) was added triethylamine trihydrofluoride (2 ml). The reaction mixture was stirred for 2 h at 70° C. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse C18 column (10-60% H₂O (0.05% NH₄HCO₃)/ACN) and then Prep-Chiral-HPLC using a CHIRALPAK IE-3, 4.6*50 mm 3 μm column (eluent: (Hex:DCM=3:1)(0.1% DEA):EtOH=60:40), Flow rate: 1 mL/min to yield (3*S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-((*R)-1-hydroxyethyl)quinoxalin-6-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as a white solid.

LC/MS: mass calculated for C₂₆H₂₂ClFN₈O₃: 548.15, measured: 549.15 [M+H]⁺. 1H NMR (300 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.84 (s, 1H), 9.02 (s, 1H), 8.46 (d, J=2.2 Hz, 1H), 7.91-8.02 (m, 2H), 7.89 (dd, J=9.1, 2.3 Hz, 1H), 7.71 (dd, J=8.7, 1.5 Hz, 1H), 5.66-5.75 (m, 2H), 4.86-5.01 (m, 1H), 4.53 (d, J=8.9 Hz, 1H), 3.67-3.79 (m, 1H), 2.51-2.58 (m, 2H), 1.96-2.23 (m, 2H), 1.6-1.84 (m, 1H), 1.49 (d, J=6.6 Hz, 3H)/¹⁹F NMR (282 MHz, DMSO-d6) δ −113.01.

Example 2: (3S*)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-((S*)-1-hydroxyethyl)quinoxalin-6-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

(3*S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-((*S)-1-hydroxyethyl)quinoxalin-6-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide was isolated as a white solid, as the second isomer from the Prep-Chiral-HPLC purification as described Example 1, above.

LC/MS: mass calculated for C₂₆H₂₂ClFN₈O₃: 548.15, measured: 549.15 [M+H]⁺. 1H NMR (300 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.84 (s, 1H), 9.02 (s, 1H), 8.47 (d, J=2.2 Hz, 1H), 7.92-8.02 (m, 2H), 7.89 (dd, J=9.1, 2.3 Hz, 1H), 7.71 (dd, J=8.7, 1.5 Hz, 1H), 5.66-5.74 (m, 2H), 4.86-5.01 (m, 1H), 4.53 (d, J=8.9 Hz, 1H), 3.66-3.79 (m, 1H), 2.51-2.58 (m, 1H), 1.98-2.26 (m, 3H), 1.67-1.82 (m, 1H), 1.49 (d, J=6.6 Hz, 3H)/¹⁹F NMR (282 MHz, DMSO-d6) δ −113.01.

Example 3: (3S*)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

To a solution of (3*S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (150 mg, 0.39 mmol, 1.0 equiv.) in pyridine (5 mL) was added 2-(2-methoxyethyl)-2H-indazol-5-amine (114 mg, 0.59 mmol, 1.5 equiv.), EDCl (152 mg, 0.79 mmol, 2.0 equiv). The resulting mixture was maintained under nitrogen and stirred at room temperature for 3 h. The reaction was concentrated and purified by preparative HPLC using a YMC-Actus Triart C18 ExRS 30 mm×150 mm×5 μm column (eluent: 25% to 39% (v/v) ACN and H₂O with 10 mmoL/L NH₄HCO₃) to yield (3S*)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3- as a white solid.

LC/MS: mass calculated for C₂₆H₂₄ClFN₈O₃: 550.16, measured: 551.05 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 9.84 (s, 1H), 8.25 (s, 1H), 8.12 (d, J=1.6 Hz, 1H), 7.97 (t, J=8.4 Hz, 1H), 7.72 (dd, J=8.7, 1.4 Hz, 1H), 7.52-7.56 (m, 1H), 7.24 (dd, J=9.2, 2.0 Hz, 1H), 5.71 (s, 1H), 4.53 (t, J=5.2 Hz, 2H), 4.49 (d, J=8.9 Hz, 1H), 3.81 (t, J=5.3 Hz, 2H), 3.74-3.69 (m, 1H), 3.22 (s, 3H), 2.54-2.47 (m, 2H), 2.16-2.05 (m, 2H), 2.01-1.92 (m, 1H), 1.77-1.73 (m, 1H)/19F NMR (376 MHz, DMSO-d6) δ −113.04.

Example 4: (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(1-(2-methoxyethyl)-1H-indazol-5-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

To a solution of (3*S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (150 mg, 0.39 mmol, 1.0 equiv.) in pyridine (7 mL) was added 2-(2-methoxyethyl)-5-nitro-2H-indazole (114 mg, 0.59 mmol, 1.50 equiv.), and EDCl (152 mg, 0.79 mmol, 2.0 equiv). The resulting mixture was maintained under nitrogen and stirred at room temperature for 3 h. The reaction was concentrated and purified by preparative HPLC using a XBridge Prep OBD C18 Column, 30×150 mm×5 μm column (eluent: 26% to 56% (v/v) ACN and H₂O with 10 mmoL/L NH₄HCO₃) to yield (3*S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(1-(2-methoxyethyl)-1H-indazol-5-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as a pink solid.

LC/MS: mass calculated for C₂₆H₂₄ClFN₈O₃: 550.16, measured: 551.05 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.84 (s, 1H), 8.10 (s, 1H), 8.01-7.92 (m, 2H), 7.72 (d, J=8.7 Hz, 1H), 7.60 (d, J=9.0 Hz, 1H), 7.46-7.39 (m, 1H), 5.71 (s, 1H), 4.55-4.46 (m, 3H), 3.77-3.70 (m, 3H), 3.17 (s, 3H), 2.54-2.47 (m, 2H), 2.22-2.05 (m, 2H), 2.01-1.92 (m, 1H), 1.81-1.70 (m, 1H)/19F NMR (376 MHz, DMSO-d6) δ −113.04.

Example 5: (3S,8aR*)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

and (3S,8aS*)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

To a solution of (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (150 mg, 0.40 mmol, 1.0 equiv.) in pyridine (6 mL) was added EDCl (92 mg, 0.60 mmol, 1.5 equiv.), and 4-amino-2-fluoro-N-(2-methoxyethyl)benzamide (126 mg, 0.60 mmol, 1.5 equiv.). The resulting mixture was stirred at room temperature for 3 h. The mixture was then concentrated. The residue obtained was purified by Prep-HPLC to yield (3S,8aR*)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as a white solid and (3S,8aS*)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as a white solid.

LC/MS: mass calculated for C₂₆H₂₄ClF₂N₇O₄: 571.1, measured: 572.05 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.85 (s, 1H), 7.94-8.12 (m, 2H), 7.55-7.79 (m, 3H), 7.34 (dd, J=8.5, 2.0 Hz, 1H), 5.73 (s, 1H), 4.48 (d, J=8.8 Hz, 1H), 3.60-3.84 (m, 1H), 3.37-3.51 (m, 4H), 3.28 (s, 3H), 2.58-2.65 (m, 1H), 2.42-2.50 (m, 1H), 2.05-2.25 (m, 2H), 1.89-2.04 (m, 1H), 1.57-1.86 (m, 1H). ¹⁹F NMR (282 MHz, DMSO-d6) δ −111.60, −113.02.

Example 6: (3S,8aR)—N-(2-Aminoquinolin-6-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

To a mixture of (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (22 mg, 0.058 mmol) and quinoline-2,6-diamine (12.1 mg, 0.076 mmol) in pyridine (2 ml) was added EDCl (16.7 mg, 0.087 mmol) and the resulting mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure and the residue was purified by HPLC to yield (3S,8aR)—N-(2-aminoquinolin-6-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as a white solid.

¹H NMR (400 MHz, METHANOL-d4) δ 9.46-9.49 (m, 1H), 8.18 (d, J=9.78 Hz, 1H), 8.15 (d, J=2.45 Hz, 1H), 7.70-7.78 (m, 2H), 7.48-7.52 (m, 1H), 7.44-7.48 (m, 1H), 6.93-6.97 (m, 1H), 5.64-5.67 (m, 1H), 4.50-4.55 (m, 1H), 3.78-3.89 (m, 1H), 2.62-2.73 (m, 1H), 2.50-2.57 (m, 1H), 2.05-2.21 (m, 3H), 1.79-1.88 (m, 1H). LC/MS calculated for C₂₅H₂₀ClFN₈O₂ 518.1, measured 519.2 (MH⁺).

Example 7: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(3,3-dimethyl-2-oxoindolin-5-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

To a mixture of (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (22.2 mg, 0.0588 mmol) and 5-amino-3,3-dimethylindolin-2-one (15.5 mg, 0.088 mmol) in a 20 ml scintillation vial was added EDCl (16.9 mg, 0.088 mmol), followed by pyridine (2 ml). The reaction mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was purified by HPLC to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(3,3-dimethyl-2-oxoindolin-5-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as a white solid.

¹H NMR (400 MHz, METHANOL-d4) δ 9.49 (s, 1H), 7.73 (dd, J=7.58, 8.56 Hz, 1H), 7.47 (dt, J=1.71, 4.28 Hz, 2H), 7.21 (dd, J=1.96, 8.31 Hz, 1H), 6.78 (d, J=8.31 Hz, 1H), 5.65 (d, J=2.93 Hz, 1H), 4.47 (d, J=8.31 Hz, 1H), 3.74-3.91 (m, 1H), 2.67-2.82 (m, 1H), 2.45-2.57 (m, 1H), 2.24 (m, 3H), 1.82-1.92 (m, 1H), 1.26 (s, 6H). LC/MS calculated for C₂₆H₂₃ClFN₇O₃: 535.2, measured 536.3 (MH⁺).

Example 8: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-N-(2′-oxospiro[cyclopentane-1,3′-indolin]-5′-yl)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

To a mixture of (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (22.2 mg, 0.06 mmol) and 5′-aminospiro[cyclopentane-1,3′-indolin]-2′-one (17.8 mg, 0.088 mmol) in a 20 ml scintillation vial was added EDCl (16.9 mg, 0.088 mmol), followed by pyridine (2 ml). The reaction mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was purified by HPLC to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-N-(2′-oxospiro[cyclopentane-1,3′-indolin]-5′-yl)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as a white solid.

¹H NMR (400 MHz, METHANOL-d4) δ 9.49 (s, 1H), 7.72 (dd, J=7.58, 8.56 Hz, 1H), 7.43-7.52 (m, 2H), 7.18 (dd, J=1.96, 8.31 Hz, 1H), 6.74 (d, J=8.31 Hz, 1H), 5.63-5.67 (m, 1H), 4.42-4.49 (m, 1H), 2.71 (br s, 1H), 2.53 (s, 1H), 1.75-2.19 (m, 13H). LC/MS calculated for C₂₈H₂₅ClFN₇O₃: 561.2, measured 562.2 (MH⁺).

Example 9: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(4-hydroxyquinolin-6-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

To a mixture of (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (22.2 mg, 0.0588 mmol) and 6-aminoquinolin-4-ol (14.6 mg, 0.088 mmol) in a 20 ml scintillation vial was added EDCl (16.9 mg, 0.088 mmol), followed by pyridine (2 ml). The reaction mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was purified by HPLC to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(4-hydroxyquinolin-6-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as a white solid.

¹H NMR (400 MHz, METHANOL-d4) δ 9.61 (s, 1H), 8.70 (d, J=2.45 Hz, 1H), 8.51 (d, J=6.36 Hz, 1H), 8.18 (dd, J=2.45, 9.29 Hz, 1H), 7.80-7.94 (m, 2H), 7.58 (dd, J=1.47, 8.80 Hz, 1H), 6.95 (d, J=6.85 Hz, 1H), 5.78 (d, J=2.93 Hz, 1H), 4.66 (d, J=8.31 Hz, 1H), 2.90-2.95 (m, 1H), 2.74-2.88 (m, 1H), 2.65-2.71 (m, 1H), 2.21-2.37 (m, 3H), 1.92-2.00 (m, 1H). LC/MS calculated for C₂₅H₁₉ClFN₇O₃: 519.1, measured 520.2 (MH⁺).

Example 10: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(3-fluoroquinolin-6-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

To a mixture of (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (22.2 mg, 0.059 mmol) and 3-fluoroquinolin-6-amine (14.3 mg, 0.088 mmol) in a 20 ml scintillation vial was added EDCl (16.9 mg, 0.088 mmol), followed by pyridine (2 ml). The reaction mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was purified by HPLC to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(3-fluoroquinolin-6-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as a white solid.

¹H NMR (400 MHz, METHANOL-d4) δ 9.61 (s, 1H), 8.73 (d, J=2.93 Hz, 1H), 8.43 (d, J=2.45 Hz, 1H), 8.02-8.10 (m, 2H), 7.77-7.91 (m, 2H), 7.58 (dd, J=1.71, 8.56 Hz, 1H), 5.78 (d, J=2.93 Hz, 1H), 4.64-4.73 (m, 1H), 4.02 (s, 1H), 2.76-2.91 (m, 1H), 2.59-2.71 (m, 1H), 2.21-2.38 (m, 3H), 1.92-2.02 (m, 1H). LC/MS calculated for C₂₅H₁₈ClF₂N₇O₂: 521.1, measured 522.2 (MH⁺).

Example 11: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-(dimethylamino)quinolin-6-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

To a mixture of (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (22.2 mg, 0.0588 mmol) and N2,N2-dimethylquinoline-2,6-diamine (14.6 mg, 0.088 mmol) in a 20 ml scintillation vial was added EDCl (16.9 mg, 0.088 mmol), followed by pyridine (2 ml). The reaction mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was purified by HPLC to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-(dimethylamino)quinolin-6-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as a white solid.

¹H NMR (400 MHz, METHANOL-d4) δ 9.51 (s, 1H), 8.09-8.29 (m, 2H), 7.68-7.88 (m, 3H), 7.47 (dd, J=1.71, 8.56 Hz, 1H), 7.26 (d, J=9.78 Hz, 1H), 5.55-5.75 (m, 1H), 4.50-4.64 (m, 1H), 3.79-3.94 (m, 1H), 3.37 (s, 6H), 2.63-2.74 (m, 1H), 2.51-2.60 (m, 1H), 2.05-2.25 (m, 3H), 1.79-1.92 (m, 1H). LC/MS calculated for C₂₇H₂₄ClFN₈O₂: 546.2, measured 547.2 (MH⁺).

Example 12: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-N-(2-oxoindolin-5-yl)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

To a mixture of (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (22.2 mg, 0.059 mmol) and 5-aminoindolin-2-one (13.1 mg, 0.088 mmol) in a 20 ml scintillation vial was added EDCl (16.9 mg, 0.088 mmol), followed by pyridine (2 ml). The reaction mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was purified by HPLC to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-N-(2-oxoindolin-5-yl)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as a light brown solid.

¹H NMR (400 MHz, METHANOL-d4) δ 9.47 (s, 1H), 7.68-7.75 (m, 1H), 7.42-7.47 (m, 1H), 7.38-7.41 (m, 1H), 7.23-7.28 (m, 1H), 6.74 (d, J=8.31 Hz, 1H), 5.64 (d, J=2.93 Hz, 1H), 4.45 (d, J=8.31 Hz, 1H), 3.73-3.86 (m, 1H), 3.43 (s, 2H), 2.64-2.76 (m, 1H), 2.44-2.53 (m, 1H), 2.02-2.18 (m, 3H), 1.80-1.88 (m, 1H). LC/MS calculated for C₂₄H₁₉ClFN₇O₃: 507.1, measured 508.1 (MH⁺).

Example 13: (3S,8aR)-7-(2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-N-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

To a mixture of (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (22.2 mg, 0.059 mmol) and 6-amino-3,4-dihydroquinolin-2(1H)-one (14.3 mg, 0.088 mmol) in a 20 ml scintillation vial was added EDCl (16.9 mg, 0.088 mmol), followed by pyridine (2 ml). The reaction mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was purified by HPLC to yield (3S,8aR)-7-(2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-N-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as an off-white solid.

¹H NMR (400 MHz, METHANOL-d4) δ 9.41-9.51 (m, 1H), 7.68-7.78 (m, 1H), 7.45 (dd, J=1.47, 8.80 Hz, 1H), 7.32 (s, 1H), 7.24 (dd, J=2.20, 8.56 Hz, 1H), 6.72 (d, J=8.31 Hz, 1H), 5.64 (d, J=2.45 Hz, 1H), 4.45 (d, J=8.80 Hz, 1H), 3.72-3.86 (m, 1H), 2.84 (t, J=7.58 Hz, 2H), 2.63-2.75 (m, 1H), 2.44-2.52 (m, 3H), 2.02-2.17 (m, 3H), 1.83 (br d, J=7.83 Hz, 1H). LC/MS calculated for C₂₅H₂₁ClFN₇O₃: 521.1, measured 522.1 (MH⁺).

Example 14: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(3-ethyl-4-oxo-3,4-dihydroquinazolin-6-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

To a mixture of (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (19.6 mg, 0.052 mmol) and 6-amino-3-ethylquinazolin-4(3H)-one hydrochloride (17.6 mg, 0.078 mmol) in a 20 ml scintillation vial was added EDCl (14.9 mg, 0.078 mmol), followed by pyridine (2 ml). The reaction mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was purified by HPLC to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(3-ethyl-4-oxo-3,4-dihydroquinazolin-6-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as a white solid.

¹H NMR (400 MHz, METHANOL-d4) δ 9.43-9.52 (m, 1H), 8.42 (d, J=2.45 Hz, 1H), 8.27 (s, 1H), 7.94 (dd, J=2.45, 8.80 Hz, 1H), 7.72 (t, J=8.07 Hz, 1H), 7.57 (d, J=8.80 Hz, 1H), 7.45 (dd, J=1.47, 8.80 Hz, 1H), 5.65 (d, J=2.93 Hz, 1H), 4.52 (d, J=9.29 Hz, 1H), 4.01 (q, J=7.01 Hz, 2H), 3.72-3.86 (m, 1H), 2.66-2.80 (m, 1H), 2.45-2.55 (m, 1H), 2.07-2.21 (m, 3H), 1.82-1.89 (m, 1H), 1.30 (t, J=7.09 Hz, 4H). LC/MS calculated for C₂₆H₂₂ClFN₈O₃ 548.1, measured 549.3 (MH⁺).

Example 15: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(3,3-difluoro-2-oxoindolin-5-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

¹H NMR (400 MHz, METHANOL-d4) δ 9.44-9.54 (m, 1H), 7.68-7.77 (m, 2H), 7.51 (br d, J=8.31 Hz, 1H), 7.45 (d, J=8.80 Hz, 1H), 6.83 (d, J=8.31 Hz, 1H), 5.64 (d, J=2.93 Hz, 1H), 4.43-4.49 (m, 1H), 3.73-3.85 (m, 1H), 2.63-2.75 (m, 1H), 2.44-2.53 (m, 1H), 2.03-2.22 (m, 3H), 1.80-1.86 (m, 1H). LC/MS calculated for C₂₄H₁₇ClF₃N₇O₃: 543.1, measured 544.2 (MH⁺).

Example 16: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

To a mixture of (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (22.2 mg, 0.0588 mmol) and 2-methyl-2H-benzo[d][1,2,3]triazol-5-amine (13.1 mg, 0.088 mmol) in a 20 ml scintillation vial was added EDCl (16.9 mg, 0.088 mmol), followed by pyridine (2 ml). The reaction mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was purified by HPLC to yield (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ 9.86 (s, 1H), 8.82 (s, 1H), 8.34 (s, 1H), 7.76 (d, J=8.80 Hz, 1H), 7.65 (t, J=7.83 Hz, 1H), 7.28-7.31 (m, 1H), 5.79 (d, J=2.45 Hz, 1H), 4.75 (d, J=7.83 Hz, 1H), 4.48 (s, 3H), 3.71-3.86 (m, 1H), 2.83 (s, 1H), 2.45-2.63 (m, 2H), 2.15-2.23 (m, 1H), 1.85-1.92 (m, 2H). LC/MS calculated for C₂₃H₁₉ClFN₉O₂: 507.1, measured 508.0 (MH⁺).

Example 17: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-N-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

¹H NMR (400 MHz, METHANOL-d4) δ 9.49 (s, 1H), 7.69-7.75 (m, 3H), 7.56 (d, J=8.80 Hz, 2H), 7.46 (dd, J=1.47, 8.80 Hz, 1H), 5.64-5.68 (m, 1H), 4.61-4.66 (m, 1H), 3.75-3.84 (m, 1H), 2.68-2.78 (m, 1H), 2.44-2.53 (m, 1H), 2.03-2.21 (m, 3H), 1.80-1.88 (m, 1H). LC/MS calculated for C₂₄H₁₈ClFN₈O₄: 536.1, measured 537.2 (MH⁺).

Example 18: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-N-(4-oxo-3,4-dihydroquinazolin-6-yl)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

To a mixture of (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (23.2 mg, 0.061 mmol) and 4-(2-methyloxazol-4-yl)aniline (22.3 mg, 0.128 mmol) in a 20 ml scintillation vial was added EDCl (17.66 mg, 0.092 mmol), followed by pyridine (2 ml). The reaction mixture was stirred at room temperature for 4 h. The solvent was removed through V-10 and the residue was purified by reverse phase HPLC to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-N-(4-oxo-3,4-dihydroquinazolin-6-yl)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as a white solid.

¹H NMR (400 MHz, METHANOL-d4) δ 10.20-10.34 (m, 1H), 9.45-9.50 (m, 1H), 8.39 (s, 1H), 7.91-7.99 (m, 2H), 7.69-7.75 (m, 1H), 7.56-7.61 (m, 1H), 7.41-7.49 (m, 1H), 5.65 (s, 1H), 4.50-4.55 (m, 1H), 3.72 (s, 1H), 2.66-2.77 (m, 1H), 2.45-2.55 (m, 1H), 2.07-2.22 (m, 2H), 1.80 (s, 1H). LC/MS calculated for C₂₄H₁₈ClFN₈O₃: 520.1, measured 521.3 (MH⁺).

Example 19: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-methyl-2H-indazol-5-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

To a mixture of (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (20 mg, 0.053 mmol) and 2-methyl-2H-indazol-5-amine (10.1 mg, 0.069 mmol) in a 20 ml scintillation vial was added EDCl (15.2 mg, 0.079 mmol), followed by pyridine (2 ml). The reaction mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was purified by HPLC to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-methyl-2H-indazol-5-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as a white solid.

¹H NMR (400 MHz, METHANOL-d4) δ 9.60 (s, 1H), 8.14-8.18 (m, 1H), 8.08-8.12 (m, 1H), 7.81-7.88 (m, 1H), 7.54-7.60 (m, 2H), 7.31 (br d, J=9.29 Hz, 1H), 5.77 (s, 1H), 4.60-4.65 (m, 1H), 4.20 (s, 3H), 3.97 (br d, J=3.42 Hz, 1H), 2.78-2.87 (m, 1H), 2.58-2.70 (m, 1H), 2.15-2.30 (m, 3H), 0.89-0.95 (m, 1H). LC/MS calculated for C₂₄H₂₀ClFN₈O₂: 506.1, measured 507.1 (MH⁺).

Example 20: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(4-(2-methyloxazol-4-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

To a mixture of (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (23.2 mg, 0.061 mmol) and 4-(2-methyloxazol-4-yl)aniline (22.3 mg, 0.128 mmol) in a 20 ml scintillation vial was added EDCl (17.66 mg, 0.092 mmol), followed by pyridine (2 ml). The reaction mixture was stirred at room temperature for 4 h. The solvent was removed through Biotage V-10 and the residue was purified by HPLC to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(4-(2-methyloxazol-4-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as a pink solid.

¹H NMR (400 MHz, METHANOL-d4) δ 9.60 (s, 1H), 8.12 (s, 1H), 7.80-7.89 (m, 1H), 7.61-7.72 (m, 4H), 7.57 (br d, J=8.80 Hz, 1H), 5.76 (br s, 1H), 4.60 (br d, J=6.85 Hz, 1H), 3.85-3.98 (m, 1H), 2.76-2.88 (m, 1H), 2.56-2.65 (m, 1H), 2.51 (s, 3H), 2.14-2.33 (m, 3H), 1.91-2.02 (m, 1H). LC/MS calculated for C₂₆H₂₁ClFN₇O₃: 533.1, measured 534.2 (MH⁺).

Example 21: (3S,8aR)—N-(1H-Benzo[d][1,2,3]triazol-5-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

To a mixture of (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (32.8 mg, 0.087 mmol) and 1H-benzo[d][1,2,3]triazol-5-amine (24.3 mg, 0.181 mmol) in a 20 ml scintillation vial was added EDCl (25 mg, 0.13 mmol), followed by pyridine (2 ml). The reaction mixture was stirred at room temperature for 4 h. The solvent was removed through Biotage V-10 and the residue was purified by HPLC to yield (3S,8aR)—N-(1H-benzo[d][1,2,3]triazol-5-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as a white solid.

¹H NMR (400 MHz, METHANOL-d4) δ 9.61 (s, 1H), 8.40 (s, 1H), 7.81-7.92 (m, 2H), 7.55-7.61 (m, 1H), 7.40-7.49 (m, 1H), 5.75-5.80 (m, 1H), 4.63-4.68 (m, 1H), 3.87-4.00 (m, 1H), 2.77-2.90 (m, 1H), 2.59-2.69 (m, 1H), 2.20-2.34 (m, 2H), 1.92-2.07 (m, 2H). LC/MS calculated for C₂₂H₁₇ClFN₉O₂: 493.1, measured 494.3 (MH⁺).

Example 22: (3S,8aS*)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₄H₁₈ClF₃NO₂: 542.12, measured (ES, m/z): 543.15 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.20 (s, 1H), 9.83 (s, 1H), 8.75 (d, J=1.0 Hz, 1H), 7.91-8.27 (m, 3H), 7.64-7.73 (m, 2H), 7.34 (dd, J=9.4, 2.0 Hz, 1H), 5.70 (s, 1H), 4.48 (d, J=9.0 Hz, 1H), 3.64-3.80 (m, 1H), 2.50-2.65 (m, 2H), 2.03-2.23 (m, 2H), 1.91-2.03 (m, 1H), 1.66-1.81 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ 84.25, −113.13.

Example 23: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₄H₁₈ClF₃NO₂: 542.12, measured (ES, m/z): 543.10 [M+H]⁺. ¹H NMR: (400 MHz, DMSO-d₆) δ 10.22 (s, 1H), 9.86 (s, 1H), 8.79 (d, J=1.0 Hz, 1H), 7.90-8.29 (m, 3H), 7.65-7.75 (m, 2H), 7.30-7.40 (m, 1H), 5.65-5.75 (m, 1H), 4.45 (t, J=8.0 Hz, 1H), 3.80-4.00 (m, 1H), 2.54-2.60 (m, 1H), 2.30-2.44 (m, 2H), 2.17-2.25 (m, 1H), 1.59-1.88 (m, 2H). ¹⁹F NMR: (376 MHz, DMSO-d₆) δ −94.26, −113.17.

Example 24: (3S,8aR)—N-(4-Carbamoyl-3-fluorophenyl)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₅H₁₈ClF₅N₆O₃: 580.10, measured (ES, m/z): 581.20 [M+H]⁺. ¹H NMR (300 MHz, Methanol-d₄) δ 9.00 (s, 1H), 7.70-7.89 (m, 3H), 7.45-7.62 (m, 1H), 7.34 (dd, J=8.5, 2.0 Hz, 1H), 5.76 (d, J=2.7 Hz, 1H), 4.61 (d, J=8.3 Hz, 1H), 4.00-3.86 (m, 1H), 2.88-2.72 (m, 1H), 2.68-2.55 (m, 1H), 2.31-2.10 (m, 3H), 1.98-1.86 (m, 1H). ¹⁹F NMR (282 MHz, Methanol-d₄) δ 62.62, −112.60, 113.77.

Example 25: (3S,8aR)—N-(4-Carbamoyl-3-fluorophenyl)-7-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₅H₁₉ClF₄N₆O₃: 562.11, measured (ES, m/z): 563.25 [M+H]⁺. ¹H NMR ¹H NMR (300 MHz, Methanol-d₄) δ 9.00 (d, J=1.0 Hz, 1H), 7.60-7.94 (m, 5H), 7.33 (dd, J=8.6, 2.0 Hz, 1H), 5.81 (d, J=2.7 Hz, 1H), 4.50-4.69 (m, 1H), 3.72-3.99 (m, 1H), 2.71-2.46 (m, 1H), 2.10-2.40 (m, 4H), 1.75-1.92 (m, 1H). ¹⁹F NMR: (282 MHz, Methanol-d₄) δ −62.57, −112.62.

Example 26: 5-[[(3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carbonyl]amino]-3-fluoro-1H-indole-2-carboxylic acid

LC/MS: mass calculated for C₂₅H₁₈ClF₂N₇O₄: 553.11, measured (ES, m/z): 554.05 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 11.61 (brs., 1H), 9.83 (s, 1H), 9.66 (s, 1H), 7.90-8.00 (m, 1H), 7.70-7.75 (m, 1H), 7.25-7.36 (m, 1H), 7.10-7.18 (m, 1H), 6.80-6.90 (m, 1H), 5.70-5.75 (m, 1H), 4.55-4.60 (m, 1H), 3.65-3.75 (m, 1H), 1.90-2.43 (m, 4H), 1.61-1.86 (m, 2H).

Example 27: (1S,3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-N-(2H-indazol-5-yl)-1-methoxy-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₅H₂₀ClFN₈O₃: 522.13, measured (ES, m/z): 523.05 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.18 (s, 1H), 9.86 (s, 1H), 8.14 (s, 1H), 7.92-8.04 (m, 2H), 7.72-7.85 (m, 1H), 7.42-7.60 (m, 2H), 5.74 (d, J=2.4 Hz, 1H), 4.40-4.58 (m, 1H), 3.85-4.10 (m, 1H), 3.50-3.60 (m, 1H), 3.30 (s, 3H), 2.54-2.78 (m, 2H), 2.30-2.35 (m, 1H), 1.99-2.03 (m, 1H). ¹⁹F-NMR (282 MHz, DMSO-d₆) δ −74.42, −113.00, −113.27.

Example 28: (1S,3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-1-methoxy-5-oxo-N-quinoxalin-6-yl-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₅H₂₀ClFN₈O₃: 534.13, measured (ES, m/z): 535.15 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.74 (s, 1H), 9.86 (s, 1H), 8.80-8.92 (m, 2H), 8.51 (s, 1H), 7.90-8.07 (m, 3H), 7.60-7.87 (m, 1H), 5.74 (s, 1H), 4.40-4.64 (m, 1H), 3.87-4.13 (m, 1H), 3.50-3.60 (m, 1H), 3.30 (s, 3H), 2.57-2.81 (m, 2H), 2.40-2.50 (m, 1H), 1.87-2.16 (m, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −73.59, −112.96, −113.08, −113.24.

Example 29: (1S,3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-1-methoxy-5-oxo-N-(6-quinolyl)-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₆H₂₁ClFN₇O₃: 533.14, measured (ES, m/z): 534.10 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.65 (s, 1H), 9.87 (s, 1H), 8.85-8.95 (m, 1H), 8.44-8.54 (m, 2H), 7.93-8.09 (m, 2H), 7.85-7.90 (m, 1H), 7.73-7.80 (m, 1H), 7.63-7.70 (m, 1H), 5.73 (s, 1H), 4.64-4.70 (m, 1H), 3.95-4.00 (m, 1H), 3.50-3.60 (m, 1H), 3.31 (s, 3H), 2.68-2.81 (m, 2H), 2.41-2.50 (m, 1H), 1.99-2.16 (m, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −74.20, −113.02, −113.30.

Example 30: (3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-hydroxy-1-oxoisoindolin-5-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₄H₁₉ClFN₇O₄: 523.12, measured (ES, m/z): 524.05 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 9.83 (d, J=3.8 Hz, 1H), 7.97 (t, J=8.3 Hz, 1H), 7.60-7.80 (m, 1H), 7.39 (d, J=8.4 Hz, 1H), 6.58-6.71 (m, 2H), 5.75 (d, J=3.1 Hz, 1H), 4.34-4.60 (m, 3H), 3.65-3.93 (m, 1H), 2.12-2.44 (m, 4H), 1.59-2.01 (m, 2H). ¹⁹F-NMR (282 MHz, DMSO-d₆) δ −74.16, −113.09

Example 31: 5-((3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamido)-N-hydroxy-N-methyl-1H-indole-2-carboxamide

LC/MS: mass calculated for C₂₆H₂₂ClFN₈O₄: 564.14, measured (ES, m/z): 565.15 [M+H]⁺. ¹H NMR (300 MHz, Methanol-d₄) δ 9.59 (s, 1H), 7.90 (s, 1H), 7.75-7.89 (m, 1H), 7.50-7.65 (m, 1H), 7.39-7.40 (m, 1H), 7.29-7.37 (m, 1H), 7.20-7.27 (m, 1H), 5.73-5.83 (m, 1H), 4.53-4.67 (m, 1H), 3.87-4.20 (m, 1H), 3.44 (s, 3H), 2.75-2.86 (m, 1H), 2.53-2.66 (m, 2H), 2.17-2.41 (m, 2H), 1.94-2.02 (m, 1H). ¹⁹F-NMR (282 MHz, Methanol-d₄) δ −77.15, −113.40, −113.91.

Example 32: (E)-3-(4-((3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamido)phenyl)acrylic acid

LC/MS: mass calculated for C₂₅H₂₀ClFN₆O₄: 522.12, measured (ES, m/z): 523.20 [M+H]⁺. ¹H NMR (300 MHz, Methanol-d₄) δ 9.59 (s, 1H), 7.77-7.89 (m, 1H), 7.52-7.67 (m, 2H), 7.49-7.55 (m, 4H), 6.35-6.50 (m, 1H), 5.75-5.80 (m, 1H), 4.51-4.65 (m, 1H), 3.83-4.18 (m, 1H), 2.75-2.89 (m, 1H), 2.54-2.65 (m, 1H), 2.43-2.52 (m, 1H), 2.13-2.28 (m, 2H), 1.87-2.03 (m, 1H)

Example 33: (3S)—N-(4-Carbamoyl-3,5-difluorophenyl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₃H₁₇ClF₃N₇O₃: 531.10, measured (ES, m/z): 532.10 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.59 (s, 1H), 9.83 (s, 1H), 7.92-8.01 (m, 2H), 7.67-7.75 (m, 2H), 7.28-7.37 (m, 2H), 5.70-5.74 (m, 1H), 4.34-4.47 (m, 1H), 3.69-3.93 (m, 1H), 2.29-2.42 (m, 1H), 2.13-2.24 (m, 1H), 2.04-2.13 (m, 1H), 1.93-2.00 (m, 1H), 1.64-1.82 (m, 2H).

Example 34: (3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(4-(hydroxy(methyl)carbamoyl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₄H₂₁ClFN₇O₄: 525.13, measured (ES, m/z): 526.15 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) 10.33 (s, 1H), 9.97 (s, 1H), 9.85 (s, 1H), 7.93-8.04 (m, 1H), 7.70-7.74 (m, 1H), 7.50-7.65 (m, 4H), 5.72 (s, 1H), 4.39-4.52 (m, 1H), 3.65-3.97 (m, 1H), 3.24 (s, 3H), 2.20-2.32 (m, 2H), 2.11-2.15 (m, 2H), 1.92-2.01 (m, 1H), 1.67-1.82 (m, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −73.41, −113.05.

Example 35: (3S,8aR*)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-N-[3-fluoro-4-(5-oxo-2H-1,2,4-oxadiazol-3-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₄H₁₇ClF₂NO₄: 554.10, measured (ES, m/z): 555.05 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 12.77 (s, 1H), 10.71 (s, 1H), 9.84 (s, 1H), 7.91-8.00 (m, 1H), 7.67-7.79 (m, 3H), 7.45-7.50 (m, 1H), 5.72 (s, 1H), 4.49 (d, J=8.9 Hz, 1H), 3.66-3.83 (m, 1H), 2.39-2.45 (m, 2H), 2.04-2.26 (m, 2H), 1.92-2.05 (m, 1H), 1.62-1.82 (m, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −108.48, −113.23.

Example 36: (3S,8aS*)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(3-fluoro-4-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-5-oxo-1,2,3,5,8,8a-_hexahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₄H₁₇ClF₂NO₄: 554.17, measured (ES, m/z): 555.05 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 12.76 (s, 1H), 10.68 (s, 1H), 9.85 (s, 1H), 7.90-8.10 (m, 1H), 7.67-7.83 (m, 3H), 7.35-7.52 (m, 1H), 5.74 (s, 1H), 4.43 (t, J=7.9 Hz, 1H), 3.81-3.99 (m, 1H), 2.52-2.61 (m, 1H), 2.30-2.49 (m, 2H), 2.12-2.30 (m, 1H), 1.60-1.88 (m, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −108.48, −113.11.

Example 37: 4-[[(3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carbonyl]amino]-2,6-difluoro-benzoic acid

LC/MS: mass calculated for C₂₃H₁₆ClF₃N₆O₄: 532.09, measured (ES, m/z): 533.20 [M+H]⁺. ¹H NMR (300 MHz, Methanol-d₄) δ 9.59 (s, 1H), 7.80-7.88 (m, 1H), 7.56-7.60 (m, 1H), 7.30-7.40 (m, 2H), 5.78 (d, J=2.8 Hz, 1H), 4.50 (t, J=8.2 Hz, 1H), 4.04-4.24 (m, 1H), 2.62-2.70 (m, 1H), 2.40-2.45 (m, 2H), 2.29-2.40 (m, 1H), 1.91-2.09 (m, 1H), 1.70-1.88 (m, 1H). ¹⁹F NMR (282 MHz, Methanol-d₄) δ −77.58, −111.12, −113.90.

Example 38: (3S)-7-(3-Chloro-6-(difluoromethoxy)-2-fluorophenyl)-5-oxo-N-(4-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₄H₁₈ClF₃N₄O₅: 534.09, measured (ES, m/z): 535.10 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.86 (s, 1H), 10.56 (s, 1H), 7.66-7.88 (m, 5H), 7.10-7.56 (m, 2H), 5.99 (s, 1H), 4.59 (d, J=8.9 Hz, 1H), 3.88-4.06 (m, 1H), 2.61-2.78 (m, 2H), 2.10-2.30 (m, 2H), 1.96-2.09 (m, 1H), 1.70-1.90 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −82.39, −113.52.

Example 39: (3S)—N-(4-Carbamoyl-3-fluorophenyl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₃H₁₈ClF₂N₇O₃: 513.11, measured (ES, m/z): 514.20 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.56 (s, 1H), 9.87 (s, 1H), 7.89-8.11 (m, 1H), 7.61-7.80 (m, 3H), 7.41-7.60 (m, 2H), 7.35-7.40 (m, 1H), 5.63-5.86 (m, 1H), 4.32-4.59 (m, 1H), 3.61-4.00 (m, 1H), 2.55-2.67 (m, 1H), 2.32-2.48 (m, 1H), 2.01-2.28 (m, 2H), 1.58-2.01 (m, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −73.42, −110.91, −113.05

Example 40: (3S)-7-(3-Chloro-2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl)-5-oxo-N-(4-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

Step 1: 2-bromo-4-chloro-3-fluoro-1-(2,2,2-trifluoroethoxy)benzene

A mixture of 2-bromo-4-chloro-3-fluorophenol (3.0 g, 13.307 mmol, 1.00 equiv), 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.633 g, 19.961 mmol, 1.50 equiv) and potassium carbonate (5.517 g, 39.921 mmol, 3.00 equiv) in DMF (50 mL) was stirred for 1 h at room temperature. The reaction was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with water and brine. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography (0-50% DCM/petroleum ether) to yield 2-bromo-4-chloro-3-fluoro-1-(2,2,2-trifluoroethoxy)benzene as a colorless oil. ¹H NMR (400 MHz, Chloroform-d) δ 7.36 (dd, J=9.0, 7.9 Hz, 1H), 6.72 (dd, J=9.0, 1.9 Hz, 1H), 4.43 (q, J=7.9 Hz, 2H).

Step 2: 2-(3-chloro-2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Under an inert atmosphere of nitrogen, a mixture of 2-bromo-4-chloro-3-fluoro-1-(2,2,2-trifluoroethoxy)benzene (2.5 g, 8.131 mmol, 1.00 equiv), bis(pinacolato)diboron (3.097 g, 12.196 mmol, 1.50 equiv), KOAc (1.995 g, 20.327 mmol, 2.50 equiv) and Pd(dppf)Cl₂ (297.471 mg, 0.407 mmol, 0.05 equiv) in 1,4-dioxane (40 mL) was stirred at 100° C. for 2 h. The resulting mixture was diluted with EtOAc (150 mL), washed with brine (4×50 mL), dried over Na₂SO₄, concentrated to yield 2-(3-chloro-2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a brown solid.

Step 3: (3S)-methyl 7-(3-chloro-2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

Under an inert atmosphere of nitrogen, a mixture of (3S)-methyl 5-oxo-7-(trifluoromethylsulfonyloxy)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (500 mg, 1.457 mmol, 1.00 equiv), 2-(3-chloro-2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (774.595 mg, 2.185 mmol, 1.50 equiv), K₂CO₃ (603.913 mg, 4.370 mmol, 3.00 equiv) and Pd(dppf)Cl₂ (106.576 mg, 0.146 mmol, 0.10 equiv) in 1,4-dioxane (15 mL) and H₂O (1.5 mL) was stirred at 90° C. for 3 h. After cooling to room temperature, the resulting mixture was diluted with EtOAc (100 mL), washed with brine (3×30 mL), dried over Na₂SO₄, concentrated. The residue was applied onto a silica gel column (40 g, EtOAc/PE: 1/1) to yield (3S)-methyl 7-(3-chloro-2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as yellow oil. LC/MS: mass calculated for C₁₈H₁₆ClF₄NO₄: 421.07, measured: 421.95 [M+H]⁺.

Step 4: (3S)-7-(3-chloro-2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

To a mixture of (3S)-methyl 7-(3-chloro-2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (500 mg, 1.185 mmol, 1.00 equiv) in MeOH (15 mL) was added a solution of LiOH (141.951 mg, 5.927 mmol, 5.00 equiv) in H₂O (5 mL). The reaction mixture was stirred at room temperature for 2 h. The pH value of the aqueous phase was adjusted to 6 used HCl solution (1 M), the resulting mixture was extracted with EtOAc (3×40 mL), dried over Na₂SO₄, concentrated to yield (3S)-7-(3-chloro-2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid as yellow solid. LC/MS: mass calculated for C₁₇H₁₄ClF₄NO₄: 407.05, measured: 407.95 [M+H]⁺.

Step 5: (3S)-7-(3-chloro-2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl)-5-oxo-N-(4-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

A mixture of (3S)-7-(3-chloro-2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (100 mg, 0.245 mmol, 1.00 equiv), 3-(4-aminophenyl)-1,2,4-oxadiazol-5(2H)-one (47.794 mg, 0.270 mmol, 1.10 equiv) and EDCl (51.717 mg, 0.270 mmol, 1.10 equiv) in pyridine (5 mL) was stirred at 30° C. overnight, then concentrated under reduced pressure. The residue was applied onto a C18 reverse column (40 g, ACN/H₂O (0.05% TFA): 5%>>>40%>>>45%) to yield (3S)-7-(3-chloro-2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl)-5-oxo-N-(4-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide as white solid.

LC/MS: mass calculated for C₂₅H₁₉ClF₄N₄O₅: 566.10, measured (ES, m/z): 567.00 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.85 (s, 1H), 10.55 (s, 1H), 7.72-7.89 (m, 4H), 7.64 (t, J=8.7 Hz, 1H), 7.05-7.20 (m, 1H), 5.86-5.98 (m, 1H), 4.81-4.97 (m, 2H), 4.45-4.65 (m, 1H), 3.84-4.14 (m, 1H), 2.55-2.71 (m, 2H), 1.97-2.45 (m, 3H), 1.67-1.93 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −72.51, −115.38.

Example 41: (3S)—N-(4-Carbamoylphenyl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₃H₁₉ClFN₇O₃: 495.12, measured (ES, m/z): 496.15 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.36 (s, 1H), 9.85 (s, 1H), 7.91-8.09 (m, 1H), 7.80-7.90 (m, 3H), 7.70-7.80 (m, 3H), 7.21-7.30 (m, 1H), 5.71-5.82 (m, 1H), 4.42-5.98 (m, 1H), 3.67-3.98 (m, 1H), 2.41-2.50 (m, 2H), 2.08-2.29 (m, 2H), 1.91-2.02 (m, 1H), 1.61-1.81 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −73.59, −113.03

Example 42: (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-N-[3-fluoro-4-(5-oxo-2H-1,2,4-oxadiazol-3-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₄H₁₇ClF₂NO₄: 554.10, measured (ES, m/z): 555.05 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 12.77 (s, 1H), 10.71 (s, 1H), 9.84 (s, 1H), 7.91-8.00 (m, 1H), 7.70-7.79 (m, 3H), 7.40-7.45 (m, 1H), 5.72 (s, 1H), 4.40-4.50 (m, 1H), 3.66-3.83 (m, 1H), 2.30-2.45 (m, 1H), 1.95-2.20 (m, 3H), 1.62-1.82 (m, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −73.40, −108.63, −113.04.

Example 43: (1R,3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-N-(2H-indazol-5-yl)-1-methoxy-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₅H₂₀ClFN₈O₃: 522.13, measured (ES, m/z): 523.20 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 12.99 (brs., 1H), 10.21 (s, 1H), 9.86 (s, 1H), 8.10-8.15 (m, 1H), 7.93-8.04 (m, 2H), 7.73-7.80 (m, 1H), 7.44-7.54 (m, 2H), 5.66-5.77 (m, 1H), 4.55-4.60 (m, 1H), 3.93-4.00 (m, 1H), 3.50-3.60 (m, 1H), 3.30 (s, 3H), 2.53-2.80 (m, 2H), 2.20-2.35 (m, 1H), 1.90-2.03 (m, 1H). ¹⁹F-NMR (282 MHz, DMSO-d₆) δ −74.43, −113.00.

Example 44: (1R,3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-1-methoxy-N-(2-methyl-2H-indazol-5-yl)-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₅H₂₂ClFN₈O₃: 536.15, measured (ES, m/z): 537.05 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.12 (s, 1H), 9.85 (s, 1H), 8.23 (s, 1H), 8.11-8.16 (m, 1H), 7.85-8.00 (m, 1H), 7.63-7.72 (m, 1H), 7.42-7.53 (m, 1H), 7.12-7.23 (m, 1H), 5.73 (d, J=2.6 Hz, 1H), 4.57-4.63 (m, 1H), 4.13 (s, 3H), 3.85-3.97 (m, 1H), 3.43-3.53 (m, 1H), 3.30 (s, 3H), 2.70-2.75 (m, 1H), 2.55-2.65 (m, 1H), 2.30-2.40 (m, 1H), 1.95-2.10 (m, 1 H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −74.16, −113.01.

Example 45: (1R,3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-1-methoxy-5-oxo-N-(6-quinolyl)-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₆H₂₁ClFN₇O₃: 533.14, measured (ES, m/z): 534.05 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.68 (s, 1H), 9.86 (s, 1H), 8.90-9.00 (m, 1H), 8.49-8.60 (m, 2H), 8.00-8.10 (m, 1H), 7.90-7.98 (m, 1H), 7.80-7.87 (m, 1H), 7.70-7.78 (m, 1H), 7.60-7.69 (m, 1H), 5.65-5.80 (m, 1H), 4.55-4.63 (m, 1H), 3.87-4.05 (m, 1H), 3.50-3.60 (m, 1H), 3.20 (s, 3H), 2.60-2.85 (m, 2H), 2.35-2.45 (m, 1H), 2.15-2.20 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −74.43, −113.03.

Example 46: (1R,3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-1-methoxy-5-oxo-N-quinoxalin-6-yl-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₅H₂₀ClFN₈O₃: 534.13, measured (ES, m/z): 535.10 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.78 (s, 1H), 9.87 (s, 1H), 8.80-8.90 (m, 2H), 8.52 (d, J=2.2 Hz, 1H), 7.90-8.10 (m, 3H), 7.70-7.80 (m, 1H), 5.70-5.80 (m, 1H), 4.60-4.69 (m, 1H), 3.90-4.00 (m, 1H), 3.50-3.60 (m, 1H), 3.25 (s, 3H), 2.60-2.80 (m, 2H), 2.40-2.50 (m, 1H), 2.00-2.15 (m, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −73.76, −113.24.

Example 47: (3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-fluoro-4-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₄H₁₇ClF₂NO₄: 554.10, measured (ES, m/z): 555.10 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ: 10.2 (s, 1H), 9.8 (s, 1H), 8.10-8.25 (m, 1H), 7.90-8.05 (m, 1H), 7.65-7.75 (m, 1H), 7.50-7.60 (m, 2H), 5.65-5.80 (m, 1H), 4.60-4.80 (m, 1H), 3.70-4.00 (m, 1H), 2.49-2.51 (m, 1H), 1.95-2.40 (m, 3H), 1.50-1.90 (m, 2H).

Example 48: (3S)—N-(4-(1H-1,2,3-triazol-1-yl)phenyl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₄H₁₉ClFN₉O₂:519.13, measured (ES, m/z): 520.20 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H), 9.86 (s, 1H), 8.78 (s, 1H), 7.94-8.02 (m, 2H), 7.76-7.92 (m, 4H), 7.70-7.75 (m, 1H), 5.61-5.80 (m, 1H), 4.37-4.57 (m, 1H), 3.70-3.98 (m, 1H), 2.27-2.47 (m, 1H), 2.05-2.28 (m, 2H), 1.95-2.05 (m, 1H), 1.54-1.91 (m, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −73.43, −113.16.

Example 49: (3S)—N-(4-(2H-1,2,3-triazol-2-yl)phenyl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₄H₁₉ClFN₉O₂: 519.13, measured (ES, m/z): 520.20 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.39 (s, 1H), 9.85 (s, 1H), 8.09 (s, 2H), 7.93-8.02 (m, 3H), 7.75-7.83 (m, 2H), 7.65-7.74 (m, 1H), 5.72 (s, 1H), 4.50 (d, J=8.9 Hz, 1H), 3.66-3.72 (m, 1H), 2.52-2.55 (m, 2H), 2.05-2.25 (m, 2H), 1.95-2.03 (m, 1H), 1.67-1.82 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −73.42, −113.04.

Example 50: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₅H₂₀ClFN₈O₃: 534.13, measured (ES, m/z): 535.10 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.45 (s, 1H), 9.85 (s, 1H), 7.89-8.04 (m, 3H), 7.74-7.83 (m, 3H), 5.72 (s, 1H), 4.51-4.60 (m, 1H), 3.69-3.79 (m, 1H), 2.65 (s, 3H), 2.62-2.64 (m, 2H), 2.27-2.31 (m, 1H), 2.09-2.18 (m, 1H), 1.94-2.08 (m, 1H), 1.72-1.81 (m, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −73.41, −113.05.

Example 51: (3S,8aS*)-4-[[7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carbonyl]amino]-2-fluoro-benzoic acid

LC/MS: mass calculated for C₂₃H₁₇ClF₂N₆O₄: 514.10, measured (ES, m/z): 515.00 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 12.98 (s, 1H), 10.64 (s, 1H), 9.85 (s, 1H), 7.96-8.01 (m, 1H), 7.85 (t, J=8.6 Hz, 1H), 7.65-7.75 (m, 2H), 7.38-7.39 (m, 1H), 5.73 (s, 1H), 4.42 (t, J=7.8 Hz, 1H), 3.78-3.98 (m, 1H), 2.54-2.59 (m, 1H), 2.28-2.47 (m, 2H), 2.13-2.25 (m, 1H), 1.60-1.86 (m, 2H).

Example 52: (3S,8R*)-4-[[7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carbonyl]amino]-2-fluoro-benzoic acid

LC/MS: mass calculated for C₂₃H₁₇ClF₂N₆O₄: 514.10, measured (ES, m/z): 515.00 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 12.98 (s, 1H), 10.66 (s, 1H), 9.85 (s, 1H), 7.94-8.03 (m, 1H), 7.85 (t, J=8.6 Hz, 1H), 7.64-7.75 (m, 2H), 7.32-7.40 (m, 1H), 5.72 (s, 1H), 4.48 (d, J=8.9 Hz, 1H), 3.66-3.79 (m, 1H), 2.48-2.53 (m, 2H), 2.06-2.25 (m, 2H), 1.90-2.06 (m, 1H), 1.60-1.80 (m, 1H).

Example 53: (3S)—N-(1H-benzo[d]imidazol-6-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₃H₁₈ClFN₈O₂: 492.12, measured (ES, m/z): 493.05 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.20-12.42 (m, 1H), 10.14 (s, 1H), 9.86 (s, 1H), 8.10-8.15 (m, 1H), 7.94-8.09 (m, 2H), 7.65-7.75 (m, 1H), 7.40-7.55 (m, 1H), 7.16-7.35 (m, 1H), 5.71 (s, 1H), 4.40-4.55 (m, 1H), 3.61-3.97 (m, 1H), 2.55-2.60 (m, 1H), 2.02-2.40 (m, 2H), 1.89-2.05 (m, 1H), 1.61-1.87 (m, 1H), 1.18-1.41 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −113.00.

Example 54: (3S)—N-(Benzo[d]oxazol-6-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₃H₁₇ClFN₇O₃:493.11, measured (ES, m/z): 494.00 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 9.85 (s, 1H), 8.66 (s, 1H), 8.22-8.25 (m, 1H), 7.94-8.01 (m, 1H), 7.73 (dd, J=8.6, 1.7 Hz, 2H), 7.42 (dd, J=8.6, 1.9 Hz, 1H), 5.69-5.76 (m, 1H), 4.43-4.52 (m, 1H), 3.89-3.96 (m, 1H), 2.51-2.60 (m, 1H), 2.25-2.40 (m, 1H), 2.05-2.25 (m, 2H), 1.95-2.01 (m, 1H), 1.64-1.86 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −113.03.

Example 55: (3S)—N-(Benzo[d]thiazol-6-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₃H₁₇ClFN₇O₂S: 509.08, measured (ES, m/z): 510.00[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.44 (s, 1H), 9.86 (d, J=1.6 Hz, 1H), 9.27 (s, 1H), 8.57-8.61 (m, 1H), 7.93-8.06 (m, 2H), 7.80-7.73 (m, 1H), 7.58-7.61 (m, 1H), 5.73 (s, 1H), 4.44-4.57 (m, 1H), 3.75-3.81 (m, 1H), 2.54-2.57 (m, 2H), 2.16-2.21 (m, 2H), 1.93-2.14 (m, 1H), 1.76-1.81 (m, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −113.09.

Example 56: (3S)—N-(2H-benzo[d][1,2,3]triazol-5-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₂H₁₇ClFN₉O₂: 493.12, measured (ES, m/z): 494.10 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.44 (s, 1H), 9.86 (s, 1H), 8.29 (s, 1H), 7.91-8.12 (m, 1H), 7.91-7.80 (m, 1H), 7.80-7.73 (m, 1H), 7.43-7.34 (m, 1H), 5.73 (s, 1H), 4.56-4.43 (m, 1H), 3.74-3.68 (m, 1H), 2.55-2.48 (m, 2H), 2.29-2.19 (m, 2H), 2.18-2.09 (m, 1H), 1.78-1.65 (m, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −113.03.

Example 57: (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-N-(3-hydroxy-1H-indazol-5-yl)-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₃H₁₈ClFN₈O₃: 508.12, measured (ES, m/z): 509.20 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 11.28 (brs., 1H), 10.06 (s, 1H), 9.85 (s, 1H), 7.92-8.08 (m, 2H), 7.56-7.80 (m, 1H), 7.32-7.43 (m, 1H), 7.08-7.27 (m, 1H), 5.69-5.80 (m, 1H), 4.48-4.51 (m, 1H), 3.67-3.78 (m, 1H), 2.31-2.42 (m, 1H), 2.05-2.28 (m, 2H), 1.92-2.03 (m, 1H), 1.50-1.90 (m, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −74.75, −113.05, −113.16.

Example 58: 4-[[(3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carbonyl]amino]-2-fluoro-benzoic acid

LC/MS: mass calculated for C₂₃H₁₇ClF₂N₆O₄: 514.10, measured (ES, m/z): 515.15 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.54 (s, 1H), 9.84 (s, 1H), 7.96-7.98 (m, 1H), 7.67-7.83 (m, 2H), 7.55-7.60 (m, 1H), 7.28-7.31 (m, 1H), 5.72 (s, 1H), 4.47 (d, J=8.9 Hz, 1H), 3.71-3.72 (m, 1H), 2.40-2.50 (m, 2H), 2.05-2.20 (m, 2H), 1.96-2.01 (m, 1H), 1.68-1.76 (m, 1H).

Example 59: (3S,8aR*)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-1,1-dimethyl-5-oxo-N-quinoxalin-6-yl-2,3,8,8a-tetrahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₆H₂₂ClFN₈O₂: 53.15, measured (ES, m/z): 533.10 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.71 (s, 1H), 9.88 (s, 1 H), 8.89 (d, J=1.9 Hz, 1H), 8.83 (d, J=1.9 Hz, 1H), 8.51 (d, J=2.3 Hz, 1H), 7.83-8.14 (m, 3H), 7.70-7.75 (m, 3H), 5.77 (d, J=1.8 Hz, 1H), 4.40-4.50 (m, 1H), 3.56-3.68 (m, 1H), 2.24-2.37 (m, 2H), 2.12-2.20 (m, 1H), 1.68-1.75 (m, 1H), 1.05 (s, 3H), 0.92 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −73.56, −112.99.

Example 60: (3S,8aR*)—N-(3-Amino-1,2-benzoxazol-6-yl)-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₃H₁₈ClFN₈O₃: 508.12, measured (ES, m/z): 509.15 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.47 (s, 1H), 9.85 (s, 1H), 7.98-8.05 (m, 1H), 7.90 (s, 1H), 7.67-7.77 (m, 2H), 7.23-7.34 (m, 1H), 6.10-6.50 (m, 2H), 5.70 (s, 1H), 4.45-4.55 (m, 1H), 3.70-3.80 (m, 1H), 2.45-2.55 (m, 2H), 2.05-2.20 (m, 2H), 1.90-2.20 (m, 1H), 1.60-1.80 (m, 1H).

Example 61: (3S,8aS*)—N-(3-Amino-1,2-benzoxazol-6-yl)-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₃H₁₈ClFN₈O₃: 508.12, measured (ES, m/z): 509.20 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.47 (s, 1H), 9.85 (s, 1H), 7.98-8.05 (m, 1H), 7.90 (s, 1H), 7.67-7.77 (m, 2H), 7.23-7.34 (m, 1H), 6.10-6.50 (m, 2H), 5.70 (s, 1H), 4.45-4.55 (m, 1H), 3.80-3.95 (m, 1H), 2.10-2.40 (m, 3H), 1.60-2.05 (m, 3H).

Example 62: (3S,8aS*)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-1,1-dimethyl-5-oxo-N-quinoxalin-6-yl-2,3,8,8a-tetrahydroindolizine-3-carboxamide

LC/MS: mass calculated for C₂₆H₂₂ClFN₈O₂: 532.15, measured (ES, m/z): 533.10 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.59 (s, 1H), 9.87 (s, 1H), 8.82-8.92 (m, 2H), 8.48 (d, J=2.3 Hz, 1H), 7.87-8.13 (m, 3H), 7.70-7.75 (m, 1H), 5.79 (d, J=2.6 Hz, 1H), 4.48 (d, J=10.7 Hz, 1H), 3.41-3.62 (m, 1H), 2.40-2.50 (m, 1H), 2.15-2.29 (m, 2H), 1.85-1.95 (m, 1H), 1.00 (d, J=3.0 Hz, 6H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −73.45, −112.81, −113.02.

Example 63: (3S,8aR*)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-N-[4-(5-oxo-2H-1,2,4-oxadiazol-3-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₄H₁₈ClFN₈O₄: 536.02, measured (ES, m/z): 537.25 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 12.86 (s, 1H), 10.51 (s, 1H), 9.85 (s, 1H), 7.92-8.00 (m, 1H), 7.68-7.84 (m, 5H), 5.72 (d, J=1.7 Hz, 1H), 4.50 (d, J=8.8 Hz, 1H), 3.69-3.79 (m, 1H), 2.54-2.58 (m, 2H), 2.32-2.45 (m, 2H), 2.05-2.22 (m, 1H), 1.60-1.80 (m, 1H).

Example 64: (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-N-(4-hydroxy-2-oxo-1H-quinolin-6-yl)-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₅H₁₉ClFN₇O₄: 535.12, measured (ES, m/z): 536.15 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 11.30 (s, 1H), 11.14 (s, 1H), 10.19 (s, 1H), 9.80-9.85 (m, 1H), 8.17-8.20 (m, 1H), 7.92-8.00 (m, 1H), 7.70-7.75 (m, 1H), 7.55-7.60 (m, 1H), 7.18-7.21 (m, 1H), 5.70-5.78 (m, 1H), 4.38-4.51 (m, 1H), 3.62-3.78 (m, 1H), 2.45-2.50 (m, 2H), 2.05-2.20 (m, 2H), 1.92-2.09 (m, 1H), 1.65-1.80 (m, 1H).

Example 65: (3S,8aS*)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-N-[4-(1H-tetrazol-5-yl)phenyl]-2,3,8,8a-tetrahydro-1_H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₃H₁₈ClFN₁₀O₂: 520.13, measured (ES, m/z): 521.20 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.48 (s, 1H), 9.86 (s, 1H), 7.92-8.04 (m, 3H), 7.77-7.86 (m, 2H), 7.70-7.75 (m, 1H), 5.74 (d, J=1.6 Hz, 1H), 4.46 (t, J=7.8 Hz, 1H), 3.88-3.99 (m, 1H), 2.53-2.57 (m, 1H), 2.30-2.43 (m, 2H), 2.17-2.28 (m, 1H), 1.67-1.88 (m, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −73.45, −113.16.

Example 66: (3S,8aR*)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-N-[4-(1H-tetrazol-5-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₃H₁₈ClFN₁₀O₂: 520.13, measured (ES, m/z): 521.20 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.47 (s, 1H), 9.85 (s, 1H), 7.93-8.04 (m, 3H), 7.77-7.87 (m, 2H), 7.70-7.75 (m, 1H), 5.72 (d, J=1.6 Hz, 1H), 4.52 (d, J=8.8 Hz, 1H), 3.69-3.80 (m, 1H), 2.45-2.50 (m, 2H), 2.05-2.28 (m, 2H), 1.95-2.03 (m, 1H), 1.69-1.82 (m, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −73.43, −113.05.

Example 67: (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-N-[4-(2-methyl-5-oxo-1,2,4-oxadiazol-3-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₅H₂₀ClFN₈O₄: 550.15, measured (ES, m/z): 551.20 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.60 (s, 1H), 9.85 (d, J=2.0 Hz, 1H), 7.95-8.00 (m, 1H), 7.79-7.88 (m, 4H), 7.67-7.81 (m, 1H), 5.69-5.77 (m, 1H), 4.48-4.52 (m, 1H), 3.79 (s, 3H), 3.70-3.78 (m, 1H), 2.50-2.54 (m, 2H), 2.06-2.25 (m, 2H), 1.90-2.00 (m, 1H), 1.62-1.80 (m, 1H).

Example 68: (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-N-[4-(1H-triazol-5-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₄H₁₉ClFN₉O₂: 519.13, measured (ES, m/z): 520.20 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 9.70 (s, 1H), 8.10-8.20 (m, 1H), 7.70-7.90 (m, 3H), 7.50-7.60 (m, 3H), 5.65 (s, 1H), 4.40-4.50 (m, 1H), 3.60-3.80 (m, 1H), 2.40-2.50 (m, 2H), 1.90-2.20 (m, 3H), 1.60-1.80 (m, 1H).

Example 69: (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-N-[4-(1H-1,2,4-triazol-3-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₄H₁₉ClFN₉O₂: 519.13, measured (ES, m/z): 520.20 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 9.72 (s, 1H), 8.38 (s, 1 H), 7.87-7.97 (m, 3H), 7.55-7.70 (m, 3H), 5.60-5.70 (m, 1H), 4.40-4.50 (m, 1H), 3.60-3.80 (m, 1H), 2.45-2.50 (m, 2H), 2.05-2.20 (m, 2H), 1.60-2.00 (m, 2H).

Example 70: (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-N-[4-(1-methyltetrazol-5-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₄H₂₀ClFN₁₀O₂: 534.14, measured (ES, m/z): 535.10 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.48 (s, 1H), 9.83 (s, 1H), 7.90-8.00 (m, 1H), 7.78-7.84 (m, 4H), 7.65-7.70 (m, 1H), 5.70 (s, 1H), 4.49 (d, J=8.9 Hz, 1H), 4.15 (s, 3H), 3.65-3.78 (m, 1H), 2.45-2.50 (m, 2H), 2.03-2.23 (m, 3H), 1.65-1.80 (m, 1H).

Example 71: (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-N-[4-(3-methyltriazol-4-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₅H₂₁ClFN₉O₂: 533.95, measured (ES, m/z): 534.10 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.36 (s, 1H), 9.83 (s, 1H), 7.90-8.00 (m, 1H), 7.84-7.86 (m, 1H), 7.70-7.80 (m, 3H), 7.50-7.60 (m, 2H), 5.70 (d, J=1.7 Hz, 1H), 4.48-5.52 (m, 1H), 4.04 (s, 3H), 3.65-3.80 (m, 1H), 2.45-2.50 (m, 2H), 2.05-2.20 (m, 2H), 1.90-2.00 (m, 1H), 1.65-1.80 (m, 1H).

Example 72: (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-N-[4-(1H-tetrazol-5-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₃H₁₈ClFN₁₀O₂: 520.13, measured (ES, m/z): 521.05 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.46 (s, 1H), 9.83 (d, J=1.6 Hz, 1H), 7.90-8.03 (m, 3H), 7.78-7.83 (m, 2H), 7.70-7.75 (m, 1H), 5.70 (d, J=1.7 Hz, 1H), 4.49 (d, J=8.8 Hz, 1H), 3.65-3.78 (m, 1H), 2.45-2.50 (m, 2H), 2.05-2.25 (m, 2H), 1.90-2.00 (m, 1H), 1.65-1.80 (m, 1H).

Example 73: (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-N-[4-(tetrazol-1-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₃H₁₈ClFN₁₀O₂: 520.13, measured (ES, m/z): 521.05 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.47 (s, 1H), 10.02 (d, J=1.8 Hz, 1H), 9.83 (s, 1H), 7.90-8.02 (m, 1H), 7.80-7.88 (m, 4H), 7.68-7.74 (m, 1H), 5.70-5.76 (m, 1H), 4.50-4.60 (m, 1H), 3.65-3.78 (m, 1H), 2.45-2.50 (m, 2H), 2.02-2.20 (m, 2H), 1.90-2.00 (m, 1H), 1.60-1.80 (m, 1H).

Example 74: (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-N-[4-(1H-imidazol-2-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₆H₂₂ClFN₈O₂: 518.14, measured (ES, m/z): 519.15 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 14.49 (s, 1H), 10.56 (s, 1H), 9.85 (s, 1H), 7.90-8.00 (m, 3H), 7.80-7.88 (m, 2H), 7.69-7.78 (m, 3H), 5.73 (d, J=2.4 Hz, 1H), 4.41-4.55 (m, 1H), 3.70-3.80 (m, 1H), 2.52-2.61 (m, 2H), 2.07-2.24 (m, 2H), 1.95-2.05 (m, 1H), 1.68-1.80 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −73.59, −113.11.

Example 75: (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-N-[4-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₄H₁₈ClFN₈O₄: 536.11, measured (ES, m/z): 537.15 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 12.49 (s, 1H), 10.48 (s, 1H), 9.85 (s, 1H), 7.98-8.10 (m, 1H), 7.68-7.82 (m, 5H), 5.72-5.80 (m, 1H), 4.50-4.60 (m, 1H), 3.74-3.80 (m, 1H), 2.40-2.50 (m, 2H), 1.90-2.20 (m, 3H), 1.60-1.80 (m, 1H).

Example 76: (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-N-[4-(5-oxo-2H-1,2,4-oxadiazol-3-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₄H₁₈ClFN₈O₄: 536.02, measured (ES, m/z): 537.05 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 12.87 (s, 1H), 10.52 (s, 1H), 9.85 (s, 1H), 7.92-8.00 (m, 1H), 7.68-7.84 (m, 5H), 5.72 (s, 1H), 4.50 (d, J=8.9 Hz, 1H), 3.70-3.80 (m, 1H), 2.45-2.50 (m, 2H), 2.05-2.15 (m, 2H), 1.94-2.04 (m, 1H), 1.60-1.80 (m, 1H).

Example 77: (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-N-[4-(1-methyl-1,2,4-triazol-3-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₅H₂₁ClFN₉O₂: 533.15, measured (ES, m/z): 534.15 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.31 (s, 1H), 9.81 (d, J=3.3 Hz, 1H), 8.49 (s, 1H), 7.89-7.98 (m, 3H), 7.63-7.71 (m, 3H), 5.69 (d, J=1.9 Hz, 1H), 4.48 (d, J=8.9 Hz, 1H), 3.89 (s, 3H), 3.72-3.75 (m, 1H), 2.32-2.48 (m, 2H), 2.04-2.32 (m, 2H), 1.93-1.97 (m, 1H), 1.64-1.77 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −74.83, −113.04, −113.16.

Example 78: (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-N-[4-(1-methylimidazol-2-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₆H₂₂ClFN₈O₂: 532.15, measured (ES, m/z): 533.10 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.60 (s, 1H), 9.83 (s, 1H), 7.93-8.01 (m, 1H), 7.83-7.90 (m, 2H), 7.68-7.82 (m, 5H), 5.71 (d, J=2.3 Hz, 1H), 4.41-4.54 (m, 1H), 3.85 (s, 3H), 3.72-3.78 (m, 1H), 2.51-2.60 (m, 1H), 2.31-2.38 (m, 1H), 2.06-2.25 (m, 2H), 1.94-2.00 (m, 1H), 1.64-1.76 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −74.15, −113.10, −113.17.

Example 79: (1S*,3S,8aS*)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-1-methyl-5-oxo-N-quinoxalin-6-yl-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₅H₂₀ClFN₈O₂: 518.14, measured (ES, m/z): 519.20 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.69 (s, 1H), 9.87 (s, 1H), 8.80-8.90 (m, 2H), 8.51 (d, J=2.3 Hz, 1H), 7.88-8.15 (m, 3H), 7.70-7.74 (m, 1H), 5.76 (d, J=2.8 Hz, 1H), 4.46 (t, J=8.4 Hz, 1H), 3.40-3.50 (m, 1H), 2.30-2.45 (m, 2H), 1.95-2.05 (m, 2H), 1.41-1.58 (m, 1H), 1.02 (d, J=6.4 Hz, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −112.99.

Example 80: (1S*,3S,8aR*)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-1-methyl-5-oxo-N-quinoxalin-6-yl-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₅H₂₀ClFN₈O₂: 518.14, measured (ES, m/z): 519.10 [M+H]⁺. ¹H NMR (300 MHz, Methanol-d₄) δ 9.55 (s, 1H), 8.80-8.90 (m, 2H), 8.59 (d, J=2.2 Hz, 1H), 8.05-8.10 (m, 1H), 7.95-8.05 (m, 1H), 7.78-7.85 (m, 1H), 7.52-7.60 (m, 1H), 5.80-5.88 (m, 1H), 4.67 (t, J=8.6 Hz, 1H), 3.86-3.96 (m, 1H), 3.43-3.58 (m, 2H), 2.95-3.11 (m, 1H), 2.55-2.65 (m, 1H), 1.67-1.79 (m, 1H), 1.11 (d, J=6.1 Hz, 3H). ¹⁹F NMR (282 MHz, Methanol-d₄) δ −114.44.

Example 81: (1R*,3S,8aR*)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-1-methyl-5-oxo-N-quinoxalin-6-yl-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₅H₂₀ClFN₈O₂: 518.14, measured (ES, m/z): 541.10 [M+Na]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.70 (s, 1H), 9.87 (s, 1H), 8.80-8.90 (m, 2H), 8.51 (d, J=2.3 Hz, 1H), 7.88-8.10 (m, 3H), 7.70-7.74 (m, 1H), 5.75 (s, 1H), 4.56 (d, J=9.2 Hz, 1H), 3.25-3.35 (m, 1H), 1.85-2.15 (m, 4H), 1.00-1.10 (m, 1H), 0.98 (d, J=6.4 Hz, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −112.86.

Example 82: (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-1-methyl-5-oxo-N-(6-quinolyl)-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₅H₂₀ClFN₈O₂: 517.14, measured (ES, m/z): 540.15 [M+Na]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 11.22 (s, 1H), 9.89 (s, 1H), 9.15-9.20 (m, 2H), 8.84 (d, J=2.2 Hz, 1H), 8.35-8.42 (m, 1H), 8.15-8.25 (m, 1H), 8.02-8.12 (m, 1H), 7.92-7.98 (m, 1H), 7.70-7.75 (m, 1H), 5.74 (d, J=2.3 Hz, 1H), 4.75-4.85 (m, 1H), 3.20-3.30 (m, 1H), 2.40-2.20 (m, 2H), 2.05-2.15 (m, 2H), 1.86-1.97 (m, 1H), 0.97 (d, J=5.7 Hz, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −112.98.

Example 83: (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-1-methyl-N-(2-methyl-2H-indazol-5-yl)-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₅H₂₂ClFN₈O₂: 520.15, measured (ES, m/z): 521.20 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.41 (s, 1H), 9.89 (s, 1H), 8.49 (s, 1H), 8.23 (d, J=1.9 Hz, 1H), 7.92-7.98 (m, 1H), 7.68-7.75 (m, 1H), 7.58-7.65 (m, 1H), 7.42-7.50 (m, 1H), 5.71 (d, J=2.1 Hz, 1H), 4.55 (d, J=9.1 Hz, 1H), 4.20 (s, 3H), 3.15-3.28 (m, 1H), 2.43-2.50 (m, 2H), 1.98-2.10 (m, 2H), 1.80-1.90 (m, 1H), 0.95 (d, J=5.9 Hz, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −112.95.

Example 84: (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-N-(2H-indazol-5-yl)-1-methyl-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₄H₂₀ClFN₈O₂: 506.14, measured (ES, m/z): 529.10 [M+Na]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 12.99 (s, 1H), 10.12 (s, 1H), 9.87 (s, 1H), 8.14 (d, J=1.8 Hz, 1H), 7.92-8.05 (m, 2H), 7.70-7.75 (m, 1H), 7.33-7.58 (m, 2H), 5.74 (s, 1H), 4.51 (d, J=9.0 Hz, 1H), 3.15-3.28 (m, 1H), 2.45-2.50 (m, 2H), 2.01-2.23 (m, 2H), 1.80-1.90 (m, 1H), 0.98 (d, J=6.2 Hz, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −112.89.

Example 85: (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-1-methyl-5-oxo-N-quinoxalin-6-yl-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide

LC/MS: mass calculated for C₂₅H₂₀ClFN₈O₂: 518.14, measured (ES, m/z): 519.20 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.70 (s, 1H), 9.88 (s, 1H), 8.80-8.90 (m, 2H), 8.51 (d, J=2.3 Hz, 1H), 7.87-8.17 (m, 3H), 7.70-7.74 (m, 1H), 5.76 (s, 1H), 4.57 (d, J=9.1 Hz, 1H), 3.20-3.30 (m, 1H), 2.45-2.55 (m, 2H), 2.10-2.20 (m, 2H), 1.87-2.01 (m, 1H), 0.99 (d, J=5.9 Hz, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −112.84.

Example 86: 5-[[(3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carbonyl]amino]-3-fluoro-1H-indole-2-carboxylic acid

LC/MS: mass calculated for C₂₄H₁₈ClFN₈O₂: 504.12, measured (ES, m/z): 505.10 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.69 (s, 1H), 9.86 (s, 1H), 8.90 (d, J=1.9 Hz, 1H), 8.83 (d, J=1.9 Hz, 1H), 8.51 (d, J=2.3 Hz, 1H), 8.06 (d, J=9.1 Hz, 1H), 7.90-8.03 (m, 2H), 7.69-7.73 (m, 1H), 5.70-5.75 (m, 1H), 4.57 (d, J=9.1 Hz, 1H), 3.72-3.80 (m, 1H), 2.52-2.58 (m, 2H), 2.16-2.29 (m, 1H), 2.10-2.20 (m, 1H), 2.00-2.10 (m, 1H), 1.70-1.85 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −73.40, −113.00.

Additional compounds of the present invention were prepared as described herein, with measured LCMS and/or ¹H NMR data for each as listed in Table 3, below.

TABLE 3 Measured Analytic Data for Representative Compounds of Formula (A) ID No. ¹H NMR and/or LC/MS 87 ¹H NMR (400 MHz, METHANOL-d4) Shift 9.56-9.63 (m, 1H), 9.08 (d, J = 2.45 Hz, 1H), 8.30 (d, J = 7.34 Hz, 1H), 7.82-7.94 (m, 3H), 7.53-7.62 (m, 1H), 6.92-7.01 (m, 1H), 5.78 (d, J = 2.93 Hz, 1H), 4.65 (d, J = 8.80 Hz, 1H), 3.89-4.02 (m, 1H), 3.58 (s, 6H), 2.72-2.84 (m, 1H), 2.63-2.71 (m, 1H), 2.16-2.36 (m, 3H), 1.91-2.02 (m, 1H). 88 ¹H NMR (400 MHz, METHANOL-d4) Shift 10.55 (s, 1H), 9.02-9.07 (m, 1H), 8.53 (s, 1H), 8.30 (d, J = 6.85 Hz, 1H), 7.89-7.94 (m, 1H), 7.77-7.85 (m, 2H), 7.50- 7.57 (m, 1H), 6.91-6.98 (m, 1H), 5.77-5.82 (m, 1H), 4.67 (d, J = 8.80 Hz, 1H), 3.93-4.05 (m, 1H), 3.56 (s, 6H), 2.76-2.86 (m, 1H), 2.59-2.68 (m, 1H), 2.15-2.39 (m, 3H), 1.91-2.04 (m, 1H). 89 ¹H NMR (400 MHz, METHANOL-d4) Shift 10.48-10.58 (m, 1H), 9.06 (t, J = 1.71 Hz, 1H), 9.02 (d, J = 0.98 Hz, 1H), 8.27-8.33 (m, 1H), 7.87-7.93 (m, 1H), 7.78-7.86 (m, 2H), 7.54-7.60 (m, 1H), 6.98 (s, 1H), 5.75-5.81 (m, 1H), 4.62-4.70 (m, 1H), 3.94-4.05 (m, 1H), 3.56 (s, 6H), 2.74-2.87 (m, 1H), 2.63-2.71 (m, 1H), 2.19-2.38 (m, 3H), 1.89-2.05 (m, 1H). 90 ¹H NMR (300 MHz, DMSO-d6) d 10.30 (s, 1H), 9.83 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.89-8.02 (m, 2H), 7.70 (dd, J = 8.7, 1.5 Hz, 1H), 7.57 (dd, J = 8.7, 2.0 Hz, 1H), 6.14 (s, 1H), 5.71 (s, 1H), 4.49 (d, J = 8.8 Hz, 1H), 3.64- 3.78 (m, 1H), 2.50-2.56 (m, 1H), 2.03-2.20 (m, 2H), 1.92-2.01 (m, 1H), 1.68-1.80 (m, 1H), 1.56 (s, 6H). 91 ¹H NMR (400 MHz, DMSO-d6) d 10.32 (s, 1H), 9.84 (s, 1H), 8.23 (d, J = 2.0 Hz, 1H), 7.93-8.01 (m, 2H), 7.72 (dd, J = 8.6, 1.5 Hz, 1H), 7.58 (dd, J = 8.7, 2.1 Hz, 1H), 6.29 (d, J = 5.1 Hz, 1H), 5.71 (s, 1H), 4.99-5.07 (m, 1H), 4.50 (d, J = 8.9 Hz, 1H), 3.70-3.76 (m, 1H), 2.53- 2.56 (m, 2H), 2.04-2.20 (m, 2H), 1.94-2.03 (m, 1H), 1.71-1.83 (m, 1H), 1.52 (d, J = 6.5 Hz, 3H) 92 ¹H NMR (400 MHz, DMSO-d6) d 10.32 (s, 1H), 9.84 (s, 1H), 8.25 (d, J = 2.1 Hz, 1H), 7.93-8.02 (m, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.57 (dd, J = 8.8, 2.1 Hz, 1H), 6.29 (d, J = 5.1 Hz, 1H), 5.72 (s, 1H), 5.08-5.00 (m, 1H), 4.50 (d, J = 8.9 Hz, 1H), 3.70-3.74 (m, 1H), 2.51-2.56 (m, 2H), 2.02-2.20 (m, 2H), 1.93-2.03 (m, 1H), 1.70-1.80 (m, 1H), 1.51 (d, J = 6.5 Hz, 3H). 93 ¹H NMR (400 MHz, DMSO-d6) d 13.12 (s, 1H), 10.32 (s, 1H), 9.36 (s, 1H), 8.02 (d, J = 9.9 Hz, 1H), 7.97 (t, J = 8.2 Hz, 1H), 7.79-7.85 (m, 2H), 7.68-7.74 (m, 3H), 6.96 (d, J = 9.9 Hz, 1H), 5.73 (s, 1H), 4.50 (d, J = 8.9 Hz, 1H), 3.67-3.79 (m, 1H), 2.55-2.57(m, 1H), 2.26- 2.36 (m, 1H), 2.05-2.22 (m, 2H), 1.94-2.02 (m, 1H), 1.67-1.79 (m, 1H). 94 ¹H NMR (300 MHz, DMSO-d6) d 10.55 (s, 1H), 9.85 (s, 1H), 7.94-8.12 (m, 2H), 7.55-7.79 (m, 3H), 7.34 (dd, J = 8.5, 2.0 Hz, 1H), 5.73 (s, 1H), 4.48 (d, J = 8.8 Hz, 1H), 3.60-3.84 (m, 1H), 3.37-3.51 (m, 4H), 3.28 (s, 3H), 2.58-2.61 (m, 1H), 2.46-2.48 (m, 1H), 2.05- 2.20 (m, 2H), 1.89-2.04 (m, 1H), 1.62-1.83 (m, 1H) 95 ¹H NMR (300 MHz, DMSO-d6) d 10.57 (s, 1H), 9.28- 9.42 (m, 1H), 7.91-8.04 (m, 1H), 7.77-7.87 (m, 1H), 7.62-7.76 (m, 3H), 7.27-7.38 (m, 1H), 5.70-5.79 (m, 1H), 4.60 (s, 1H), 4.50 (d, J = 8.9 Hz, 1H), 3.66- 3.83(m, 1H), 3.25 (d, J = 5.9 Hz, 2H), 2.55-2.60 (m, 1H), 2.33-2.48 (m, 1H), 2.04-2.25 (m, 2H), 1.88- 2.04 (m, 1H), 1.60-1.80 (m, 1H), 1.13 (s, 6H). 96 ¹H NMR (400 MHz, METHANOL-d4) Shift 7.67-7.76 (m, 1H), 7.45 (dd, J = 1.47, 8.80 Hz, 1H), 7.17 (s, 2H), 6.80-6.84 (m, 1H), 5.64 (d, J = 2.93 Hz, 1H), 4.43-4.48 (m, 1H), 3.71-3.85 (m, 1H), 2.62-2.78 (m, 1H), 2.44- 2.60 (m, 1H), 2.01-2.20 (m, 3H), 1.77-1.90 (m, 1H), 1.48-1.58 (m, 4H). 97 LC/MS calculated for C₂₅H₁₈CIF₃N₈O₃ 570.1, measured 571.2 (MH⁺). 98 LC/MS (m/z): 521.2 (MH⁺) 99 ¹H NMR (400 MHz, METHANOL-d4) Shift 9.59 (s, 1H), 7.77-7.89 (m, 4H), 7.66 (d, J = 8.31 Hz, 2H), 7.57 (d, J = 8.80 Hz, 1H), 5.74-5.81 (m, 1H), 4.57-4.66 (m, 1H), 3.88-3.99 (m, 1H), 2.73-2.85 (m, 1H), 2.68 (s, 1H), 2.12-2.30 (m, 2H), 1.89-1.98 (m, 1H). LC/MS calculated for C₂₃H₂₀CIFN₈O₃: 510.1, measured (MH⁺). 100 ¹H NMR (400 MHz, METHANOL-d4) Shift 9.60 (s, 1H), 7.84 (t, J = 8.07 Hz, 1H), 7.70 (d, J = 8.31 Hz, 2H), 7.57 (d, J = 8.80 Hz, 3H), 5.76 (d, J = 2.45 Hz, 1H), 4.61 (d, J = 8.31 Hz, 1H), 3.86-3.98 (m, 1H), 2.77-2.88 (m, 2H), 2.57-2.67 (m, 1H), 2.12-2.34 (m, 4H), 1.84-2.01 (m, 1H), 0.97 (q, J = 6.52 Hz, 2H), 0.69-0.78 (m, 2H). 101 LC/MS (m/z): 493.3 (MH⁺) 102 ¹H NMR (400 MHz, Methanol-d4) d 8.99 (s, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.47-7.59 (m, 1H), 7.10-7.22 (m, 2H), 6.95-7.06 (m, 1H), 5.76 (d, J = 2.7 Hz, 1H), 4.59 (d, J = 8.0 Hz, 1H), 3.80-4.01 (m, 1H), 3.43-3.53 (m, 1H), 2.73-2.88 (m, 1H), 2.51-2.66 (m, 1H), 2.14- 2.35 (m, 3H), 1.84-1.99 (m, 1H), 1.39-1.48 (m, 3H). 103 ¹H NMR (400 MHz, METHANOL-d4) Shift 9.00 (s, 1H), 8.16-8.23 (m, 1H), 7.82 (dd, J = 7.58, 8.56 Hz, 1H), 7.68-7.75 (m, 1H), 7.55 (dd, J = 1.71, 8.56 Hz, 1H), 7.23 (t, J = 8.07 Hz, 1H), 5.78 (d, J = 2.93 Hz, 1H), 4.68 (t, J = 8.07 Hz, 1H), 4.12-4.23 (m, 1H), 2.67-2.72 (m, 1H), 2.49-2.60 (m, 2H), 2.33-2.41 (m, 1H), 2.02-2.10 (m, 1H), 1.76-1.86 (m, 1H). 104 ¹H NMR (400 MHz, METHANOL-d4) Shift 10.00 (s, 1H), 9.00 (d, J = 0.98 Hz, 1H), 7.81 (dd, J = 7.58, 8.56 Hz, 1H), 7.61 (s, 1H), 7.54 (dd, J = 1.47, 8.80 Hz, 1H), 7.44 (td, J = 1.83, 8.07 Hz, 1H), 7.19 (d, J = 7.83 Hz, 1H), 5.77 (d, J = 2.93 Hz, 1H), 4.52 (t, J = 8.31 Hz, 1H), 4.12- 4.23 (m, 1H), 4.02 (t, J = 7.58 Hz, 1H), 3.00-3.10 (m, 1H), 2.85-2.95 (m, 1H), 2.63-2.71 (m, 1H), 2.30-2.56 (m, 6H), 1.94-2.05 (m, 1H), 1.82 (s, 1H). 105 ¹H NMR (400 MHz, METHANOL-d4) Shift 10.28-10.33 (s, 1H), 8.53 (s, 1H), 8.33 (d, J = 2.45 Hz, 1H), 7.77-7.84 (m, 2H), 7.51 (dd, J = 1.47, 8.80 Hz, 1H), 7.42-7.47 (m, 1H), 5.79 (d, J = 2.93 Hz, 1H), 4.58 (t, J = 8.31 Hz, 1H), 4.48 (s, 3H), 4.20 (br d, J = 4.40 Hz, 1H), 2.62-2.70 (m, 1H), 2.47-2.58 (m, 2H), 2.37 (s, 1H), 1.99-2.10 (m, 1H), 1.73-1.85 (m, 1H). 106 ¹H NMR (400 MHz, CHLOROFORM-d) Shift 9.88-9.95 (m, 1H), 8.39 (br d, J = 2.93 Hz, 1H), 8.10-8.14 (m, 1H), 7.75 (d, J = 8.80 Hz, 1H), 7.63 (dd, J = 7.58, 8.56 Hz, 1H), 7.28 (d, J = 1.96 Hz, 1H), 7.20-7.25 (m, 1H), 5.74- 5.78 (m, 1H), 4.74-4.81 (m, 1H), 4.48 (s, 3H), 3.73-3.89 (m, 1H), 2.75-2.82 (m, 1H), 2.55-2.61 (m, 1H), 2.15- 2.23 (m, 1H), 1.85-1.93 (m, 2H). 107 LC/MS (m/z): 659.2 (MH⁺) 108 ¹H NMR (300 MHz, Methanol-d4) d 9.00 (s, 1H), 7.89- 7.70 (m, 3H), 7.57 (dd, J = 8.7, 1.6 Hz, 1H), 7.34 (dd, J = 8.5, 2.0 Hz, 1H), 5.76 (d, J = 2.7 Hz, 1H), 4.61 (d, J = 8.3 Hz, 1H), 4.41-4.39 (m, 1H), 2.88-2.72 (m, 1H), 2.68-2.55 (m, 1H), 2.31-2.10 (m, 3H), 1.98-1.86 (m, 1H). 109 ¹H NMR (300 MHz, Methanol-d4) d 9.00 (s, 1H), 7.89- 7.63 (m, 5H), 7.33 (dd, J = 8.6, 2.1 Hz, 1H), 5.81 (d, J = 2.7 Hz, 1H), 4.62 (d, J = 8.6 Hz, 1H), 3.93-3.79 (m, 1H), 2.51-2.19 (m, 4H), 2.05-1.88(m, 1h), 1.72- 1.53 (m, 1H) 110 ¹H NMR (300 MHz, DMSO-d6) (ppm)d: 10.11 (s, 1H), 9.86 (s, 1H), 8.24 (s, 1H), 8.13-8.20 (m, 1H), 7.98- 8.05 (m, 1H), 7.72-7.80 (m, 1H), 7.54-7.60 (m, 1H), 7.19-7.30 (m, 1H), 5.71 (s, 1H), 4.57-4.60 (m, 1H), 4.13 (s, 3H), 3.85-3.99 (m, 2H), 3.30 (d, J = 6.3 Hz, 3H), 2.52-2.77 (m, 2H), 2.35-2.40 (m, 1H), 1.91- 2.11(m, 1H). 111 ¹H NMR (300 MHz, DMSO-d6) d(ppm): 11.12 (s, 1H), 10.36 (s, 1H), 9.85 (s, 1H), 7.93-8.04(m, 1H), 7.58- 7.80(m, 5H), 5.72 (s, 1H), 4.40-4.53 (m, 1H), 3.64-3.91 (m, 1H), 1.90-2.39 (m, 4H), 1.59-1.84 (m, 2H).

BIOLOGICAL AND FORMULATION EXAMPLES Biological Example 1: Factor XIa Inhibition Assay Utilizing a Fluorophore-Quencher Pair Peptide Substrate

A fluorescence intensity (FLINT) based assay was used to monitor inhibition of Factor XIa. The peptide substrate, 5Fam-KLTRAETV-K5Tamra (purchased from New England Peptide) was chosen based on the FXI sequence. Conversion of zymogen FXI to its activated form, FXIa, occurs by proteolytic cleavage by FXIa at two sites, Arg146 and Arg180. The custom peptide used in this assay was based on the Arg146 cleavage site of FXI. The peptide substrate was designed with a fluorophore-quencher pair, where the fluorescence is quenched until FXIa cleaves the 8-mer peptide after the Arg residue. The substrate K_(M) was fit to a substrate inhibition model whereby k_(cat)=0.86 s⁻¹, K_(M)=12.4 μM, K_(i)=61.6 μM with an enzymatic efficiency, and k_(cat)/K_(M)=69523 M⁻¹s⁻¹.

The Factor XIa FLINT assay was used with the following 5Fam-KLTRAETV-K5Tamra assay buffer: 50 mM Tris, pH 7.5, 100 mM NaCl, 5 mM CaCl₂, 0.1 mg/mL BSA, 0.03% CHAPS. Assay buffer was prepared by mixing all ingredients fresh. 5Fam-KLTRAETV-K5Tamra peptide substrate was first prepared at 10 mM in 100% DMSO, then diluted to 3 mM in 100% DMSO. Assay buffer was then added directly to the 3 mM stock of substrate to prepare the 30 μM 2× working concentration (15 μM final concentration). The 2× Factor XIa stock solution was prepared by diluting 6.562 μM stock in 1× assay buffer for a 200 μM working stock solution (100 μM final concentration).

Test compound(s) were run in an 11-point, 3-fold serial dilution with a final top compound concentration of 100 nM. Final DMSO in assay was 2%. FXIa was preincubated with compound for 30-minutes and then substrate was added to initiate the reaction. The assay was run with kinetic (KIN) reads at 5 min intervals over 30 minutes. The time course was linear using 100 μM FXIa greater than 30 minutes. More specifically, the assay was run as follows:

-   -   100 nL of 0.01 mM test compound was dispensed into black         384-well non-binding Greiner BioOne 784900 plate for 0.1 μM         final concentration,     -   5 μL of 1× assay buffer was dispensed to column 24 (low control)         and 5 μL 2× Factor XIa solution was dispensed to columns 1-23         (column 23 high control);     -   the plate was centrifuged with a “cover” plate at 500 rpm for 1         min     -   the plate was pre-incubated for 30 minutes at room temperature         with plate covered;     -   5 μL of 2×5Fam-KLTRAETV-K5Tamra peptide substrate was dispensed         into the entire plate, columns 1-24;     -   the plate was centrifuged with a “cover” plate at 500 rpm for 1         min;     -   the plate was read monitoring fluorescence intensity on the BMG         PHERAStar at room temperature, using fluorescence module 485         nm/520 nm.

Percent inhibition (IC₅₀) curves were generated per compound tested, and data was analyzed using a 4-parameter logistic fit using GeneData Screener. The relative fluorescence unit (RFU) values were normalized to percent inhibition using the following equation:

% inhibition=((HC−LC)−(compound−LC)/(HC−LC))*100

where LC−low control=mean signal of no Factor XIa or 100% inhibition of Factor XIa; HC−high control=mean signal of Factor XIa+5Fam-KLTRAETV-K5Tamra peptide substrate with DMSO only.

An 11-point dose response curve for the test compound(s) was generated using GENDATA to determine IC₅₀ value based on the following equation:

Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((log IC₅₀ −X)*HillSlope))

where Y is the % inhibition in the presence of X inhibitor concentration, Top=high control=mean signal of Factor XIa+5Fam-KLTRAETV-K5Tamra peptide substrate with DMSO only; Bottom=low control−mean signal of no Factor XIa or 100% inhibition of Factor XIa; HillSlope−Hill coefficient; and IC₅₀=concentration of compound with 50% inhibition in relation to top/high control.

Biological Example 2: Kallikrein Inhibition Assay Utilizing a Quenched AMC Peptide Substrate

A fluorescence intensity (FLINT) based assay was used to monitor inhibition of human plasma kallikrein. The peptide substrate, Z-Gly-Pro-Arg-AMC (Purchased from Bachem; Catalog #I-1150) was chosen based on its relatively low K_(M) for kallikrein which enables running the assay at lower substrate concentrations to control background fluorescence. The kinetic parameters for this substrate were determined by fitting titration data to the Michaelis-Menten equation yielding a K_(M)=40 μM, k_(cat)=0.76 s⁻¹, and k_(cat)/K_(M)=18932 M⁻¹s⁻¹.

The Kallikrein FLINT assay was used with the following Z-Gly-Pro-Arg-AMC assay buffer: 50 mM Tris, pH 7.5, 100 mM NaCl, 5 mM CaCl₂, 0.1 mg/mL BSA, 0.03% CHAPS. Assay buffer was prepared by mixing all ingredients fresh. 2× Z-Gly-Pro-Arg-AMC peptide substrate was prepared by diluting 10 mM stock into 1× assay buffer for a 100 μM working concentration (50 μM final concentration). The 2× kallikrein stock solution was prepared by diluting 14.76 μM stock in 1× assay buffer for a 4 nM working stock solution (2 nM final concentration).

Test compound(s) were run in an 11-point, 3-fold serial dilution with a final top compound concentration of 1 μM. Final DMSO in assay was 2%. Plasma kallikrein was pre-incubated for 30-minute with compound and then 50 μM substrate was added to initiate the reaction. The assay was run with kinetic (KIN) reads at 5 min intervals over 30 minutes. The time course was linear using 2 nM kallikrein greater than 30 minutes. More specifically, the assay was run as follows:

-   -   100 nL of 0.1 mM test compound was dispensed into black 384-well         non-binding Greiner BioOne 784900 plate for 1 μM final         concentration;     -   5 μL of 1× assay buffer was dispensed to columns 24 (low         control) and 5 μL 2× human kallikrein enzyme solution was         dispensed to columns 1-23 (column 23 high control);     -   the plate was centrifuged with a “cover” plate at 500 rpm for 1         min     -   the plate was pre-incubated for 30 minutes at room temperature         with plate covered;     -   5 μL of 2× Z-Gly-Pro-Arg-AMC peptide substrate was dispensed         into the entire plate, columns 1-24;     -   the plate was centrifuged with a “cover” plate at 500 rpm for 1         min;     -   the plate was read monitoring fluorescence intensity on the BMG         PHERAStar at room temperature, using fluorescence module 340         nm/440 nm.

Percent inhibition (IC₅₀) curves were generated per compound tested, and data was analyzed using a 4-parameter logistic fit using GeneData Screener. The relative fluorescence unit (RFU) values were normalized to percent inhibition using the following equation:

% inhibition=((HC−LC)−(compound−LC)/(HC−LC))*100

where LC−low control=mean signal of human kallikrein enzyme or 100% inhibition of human kallikrein enzyme; HC−high control=mean signal of Factor XIa+Z-Gly-Pro-Arg-AMC peptide substrate with DMSO only.

An 11-point dose response curve for the test compound(s) was generated using GENDATA to determine IC₅₀ value based on the following equation:

Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((log IC₅₀ −X)*HillSlope))

where Y is the % inhibition in the presence of X inhibitor concentration, Top=high control=mean signal of human kallikrein enzyme+Z-Gly-Pro-Arg-AMC peptide substrate with DMSO only; Bottom=low control−mean signal of no human kallikrein enzyme or 100% inhibition of human kallikrein enzyme; HillSlope−Hill coefficient; and IC₅₀=concentration of compound with 50% inhibition in relation to top/high control.

Representative compounds of formula (I) of the present invention were tested according to the procedure described in Biological Example 1 and Biological Example 2 above, with results as listed in Table 3, below.

TABLE 3 Biological Activity, Representative Compounds of Formula (I) FXIa Inhibition Plasma Kallikrein ID No. IC₅₀ (nM) IC₅₀ (nM) 1 5.0 9.7 2 6.4 11.3 3 6.0 35.6 4 26.9 106.4 5 15.5 127.5 6 8.0 14.3 7 65.0 130.6 8 62.1 178.4 9 16.6 20.2 10 10.8 22.5 11 38.8 66.2 12 18.2 71.7 13 12.9 68.4 14 22.7 59.6 15 36.8 55.7 16 25.0 45.3 17 3.4 60.1 18 6.1 9.2 19 39.4 168.6 20 25.9 112.2 21 9.1 37.4 22 4.2 19.3 23 8.3 31.1 24 38.2 76.1 25 28.1 116.4 26 3.2 60.4 27 136.2 1.03 μM 28 ~189.1 430.6 29 180.4 611.4 30 >95 128.1 31 4.8 23.7 32 1.6 14.4 33 24.0 203.8 34 36.3 279.3 35 0.4 6.4 36 0.4 8.8 37 5.8 281.6 38 40.2 421.4 39 7.5 53.0 40 30.8 1.33 μM 41 7.4 79.7 42 0.3 10.0 43 11.0 31.3 44 10.9 31.4 45 7.8 14.0 46 5.3 12.3 47 23.3 274.0 48 21.4 86.3 49 30.5 54.2 50 31.8 57.0 51 2.5 149.2 52 0.9 70.8 53 11.1 56.2 54 11.5 59.0 55 6.6 27.7 56 5.4 19.0 57 16.7 36.1 58 1.2 107.2 59 82.9 38.8 60 6.7 29.7 61 8.9 52.6 62 13.3 17.2 63 0.6 20.3 64 3.0 9.5 65 1.9 36.6 66 0.8 19.2 67 182.9 1.56 μM 68 1.7 47.1 69 7.3 52.3 70 84.8 436.3 71 46.0 155.8 72 0.7 20.4 73 26.3 155.7 74 2.0 40.7 75 1.8 11.2 76 0.3 22.2 77 8.0 63.5 78 58.4 1.01 μM 79 3.9 7.5 80 45.9 59.5 81 639.4 1.05 μM 82 7.9 8.0 83 17.8 27.0 84 19.3 27.8 85 9.9 12.2 86 4.2 14.3 87 20.8 64.9 88 >50 160.0 89 >50 637.4 90 >50 108.8 91 >50 115.2 92 33.5 50.4 93 >50 396.3 94 >50   >1 μM 95 >50 593.2 96 42.2 127.5 97 >50 348.4 98 23.4 123.5 99 26.1 606.0 100 >50 677.3 101 NT^(a) NT^(a) 102 >50 570.3 103 >50   >1 μM 104 >50   >1 μM 105 >50 120.0 106 >50 497.3 107 >50 189.6 108 >50 626.3 109 >50 946.2 110 >100 1.17 μM 111 NT^(a) NT^(a) NT^(a) indicates that the compound was not tested.

Formulation Example 1 Solid, Oral Dosage Form—Prophetic Example

As a specific embodiment of an oral composition, 100 mg of any of Compound ID No. 35, 36, 52, 63 or 68, prepared as described in Examples 35, 36, 52, 63 and 68, respectively, is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

Throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains. 

1. The compound of formula (A)

wherein R¹ is selected from the group consisting of halogen, hydroxy, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy, cyano, nitro, —NR^(A)R^(B), —C(O)—C₁₋₄alkyl, C₃₋₆cycloalkyl, phenyl and 5- to 6-membered heterocyclyl; wherein the C₃₋₆cycloalkyl, phenyl or 5- to 6-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —NR^(A)R^(B), −(C₁₋₄alkyl)-NR^(A)R^(B), C₃₋₇cycloalkyl and 5- to 6-membered heterocyclyl; wherein R^(A) and R^(B) are each independently selected from the group consisting of hydrogen and C₁₋₄alkyl; a is an integer from 0 to 3; each R² is independently selected from the group consisting of chloro, fluoro, methyl and methoxy; R³ is selected from the group consisting of hydrogen and C₁₋₄alkyl; R⁴ is selected from the group consisting of hydrogen, C₁₋₄alkyl and C₁₋₄alkoxy; Q is selected from the group consisting of (a) phenyl; wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C₂₋₄alkynyl, carboxy substituted C₂₋₄alkynyl, C₁₋₄alkoxy, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —C(O)—NR^(C)R^(D), 5- to 6-membered heteroaryl and 5- to 6-membered heterocycloalkyl; wherein R^(C) is selected from the group consisting of hydrogen and C₁₋₄alkyl; and R^(D) is selected from the group consisting of hydrogen, hydroxy, C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, —(C₁₋₂alkylene)-O—(C₁₋₄alkyl), and cyclopropyl; and wherein the 5- to 6-membered heteroaryl or 5- to 6-membered heterocycloalkyl is further optionally substituted with one to two substituents independently selected from the group consisting of C₁₋₂alkyl, fluorinated C₁₋₂alkyl, and oxo; provided that no more than one substituent on the phenyl is optionally substituted 5- to 6-membered heteroaryl or 5- to 6-membered heterocycloalkyl; (b) 9- to 10-membered nitrogen containing heterocyclyl; wherein the 9- to 10-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, —C(O)OH, —C(O)O—(C₁₋₄alkyl), C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, fluorinated C₁₋₄alkyl, —(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —O—(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —NR^(E)R^(F) and —C(O)—NR^(E)R^(F); wherein R^(E) is selected from the group consisting of hydrogen, and C₁₋₄alkyl; and R^(F) is selected from the group consisting of hydrogen, hydroxy, and C₁₋₄alkyl; and

 wherein b is an integer from 1 to 3; or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.
 2. The compound of claim 1 of the formula (I)

wherein R¹ is selected from the group consisting of halogen, hydroxy, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy, cyano, nitro, —NR^(A)R^(B), —C(O)—C₁₋₄alkyl, C₃₋₆cycloalkyl, phenyl and 5- to 6-membered heterocyclyl; wherein the C₃₋₆cycloalkyl, phenyl or 5- to 6-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —NR^(A)R^(B), —(C₁₋₄alkyl)-NR^(A)R^(B), C₃₋₇cycloalkyl and 5- to 6-membered heterocyclyl; wherein R^(A) and R^(B) are each independently selected from the group consisting of hydrogen and C₁₋₄alkyl; a is an integer from 0 to 3; each R² is independently selected from the group consisting of chloro, fluoro, methyl and methoxy; R³ is selected from the group consisting of hydrogen and C₁₋₄alkyl; R⁴ is selected from the group consisting of hydrogen, C₁₋₄alkyl and C₁₋₄alkoxy; Q is selected from the group consisting of (a) phenyl; wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C₂₋₄alkynyl, carboxy substituted C₂₋₄alkynyl, C₁₋₄alkoxy, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —C(O)—NR^(C)R^(D), 5- to 6-membered heteroaryl and 5- to 6-membered heterocyloalkyl; wherein R^(C) is selected from the group consisting of hydrogen and C₁₋₄alkyl; and R^(D) is selected from the group consisting of hydrogen, hydroxy, C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, —(C₁₋₂alkylene)-O—(C₁₋₄alkyl), and cyclopropyl; and wherein the 5- to 6-membered heteroaryl or 5- to 6-membered heterocycloalkyl is further optionally substituted with one to two substituents independently selected from the group consisting of C₁₋₂alkyl, fluorinated C₁₋₂alkyl, and oxo; provided that no more than one substituent on the phenyl is optionally substituted 5- to 6-membered heteroaryl to 5- to 6-membered heterocycloalkyl; (b) 9- to 10-membered nitrogen containing heterocyclyl; wherein the 9- to 10-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, —C(O)OH, —C(O)O—(C₁₋₄alkyl), C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, fluorinated C₁₋₄alkyl, —(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —O—(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —NR^(E)R^(F) and —C(O)—NR^(E)R^(F); wherein R^(E) is selected from the group consisting of hydrogen, and C₁₋₄alkyl; and R^(F) is selected from the group consisting of hydrogen, hydroxy, and C₁₋₄alkyl; and

 wherein b is an integer from 1 to 3; or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.
 3. The compound of claim 1, wherein R¹ is selected from the group consisting of halogen, hydroxy, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy, cyano, nitro, —NR^(A)R^(B), —C(O)—C₁₋₄alkyl, and 5- to 6-membered heterocyclyl; wherein the 5- to 6-membered heterocyclyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —NR^(A)R^(B) and —(C₁₋₂alkyl)-NR^(A)R^(B); wherein R^(A) and R^(B) are each independently selected from the group consisting of hydrogen and C₁₋₂alkyl; a is an integer from 1 to 3; each R² is independently selected from the group consisting of chloro, fluoro, methyl and methoxy; R³ is selected from the group consisting of hydrogen and C₁₋₄alkyl; R⁴ is selected from the group consisting of hydrogen, C₁₋₄alkyl and C₁₋₄alkoxy; Q is selected from the group consisting of (a) phenyl; wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, carboxy substituted C₂₋₄alkynyl, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —C(O)—NR^(C)R^(D), 5- to 6-membered heteroaryl and 5- to 6-membered heterocycloalkyl; wherein R^(C) is selected from the group consisting of hydrogen and C₁₋₄alkyl; and R^(D) is selected from the group consisting of hydrogen, hydroxy, C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, —(C₁₋₂alkylene)-O—(C₁₋₄alkyl), and cyclopropyl; and wherein the 5- to 6-membered heteroaryl is further optionally substituted with one to two substituents independently selected from the group consisting of C₁₋₄alkyl, fluorinated C₁₋₂alkyl, and oxo; provided that no more than one substituent on the phenyl is optionally substituted 5- to 6-membered heteroaryl or 5- to 6-membered heterocycloalkyl; (b) 9- to 10-membered nitrogen containing heterocyclyl; wherein the 9- to 10-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, —C(O)OH, —C(O)O—(C₁₋₄alkyl), C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, fluorinated C₁₋₄alkyl, —(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —O—(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —NR^(E)R^(F) and —C(O)—NR^(E)R^(F); wherein R^(E) is selected from the group consisting of hydrogen, and C₁₋₄alkyl; and R^(F) is selected from the group consisting of hydrogen, hydroxy, and C₁₋₄alkyl; and

 wherein b is an integer from 1 to 3; or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.
 4. The compound of claim 1, wherein R¹ is selected from the group consisting of fluorinated C₁₋₂alkyl, triazolyl and tetrazolyl; wherein the triazolyl is optionally substituted with halogen or fluorinated C₁₋₂alkyl; a is an integer from 1 to 2; each R² is independently selected from chloro and fluoro; R³ is selected from the group consisting of hydrogen and C₁₋₂alkyl; R⁴ is selected from the group consisting of hydrogen, C₁₋₂alkyl and C₁₋₂alkoxy; Q is selected from the group consisting of (a) phenyl; wherein the phenyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, carboxy substituted C₂₋₄alkynyl, —C(O)OH, —C(O)—NR^(C)R^(D), —C(═NH)—NH(OH), 5-membered nitrogen containing heteroaryl and 5- to 6-membered nitrogen containing heterocycloalkyl; wherein R^(C) is selected from the group consisting of hydrogen and C₁₋₂alkyl; and R^(D) is selected from the group consisting of hydrogen, hydroxy, hydroxy substituted C₁₋₄alkyl, —(C₁₋₂alkylene)-O—(C₁₋₂alkyl) and cyclopropyl; wherein the 5 membered nitrogen containing heteroaryl or 5- to 6-membered nitrogen containing heterocycloalkyl is optionally substituted with one to two substituents independently selected from the group consisting of C₁₋₂alkyl, fluorinated C₁₋₂alkyl, oxo; provided that no more than substituent on the phenyl is optionally substituted 5-membered, nitrogen containing heteroaryl or 5- to 6-membered nitrogen containing heterocycloalkyl; (b) 9- to 10-membered nitrogen containing heterocyclyl; wherein the 9- to 10-membered heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, —C(O)OH, C₁₋₂alkyl, hydroxy substituted C₁₋₄alkyl, fluorinated C₁₋₂alkyl, —(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —O—(C₁₋₂alkylene)-O—(C₁₋₂alkyl), —NR^(E)R^(F) and —C(O)—NR^(E)R^(F); wherein R^(E) is selected from the group consisting of hydrogen, and C₁₋₂alkyl; and R^(F) is selected from the group consisting of hydrogen, hydroxy, C₁₋₂alkyl; and

 wherein b is an integer from 1 to 3; or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.
 5. The compound of claim 1, wherein R¹ is selected from the group consisting of difluoromethoxy, 2,2,2-trifluoroethoxy, 4-chloro-1,2,3-triazol-1-yl, 4-(trifluoromethyl)-1,2,3-triazol-1-yl, 1,2,3,4-tetrazol-1-yl and 5-deutero-1,2,3,4-tetrazol-1-yl; a is an integer from 1 to 2; each R² is independently selected from the group consisting of 2-fluoro, and 3-chloro; R³ is selected from the group consisting of hydrogen and methyl; R⁴ is selected from the group consisting of hydrogen, methyl, S*-methyl, R*-methyl, S-methoxy and R-methoxy; Q is selected from the group consisting of (a) 2-fluoro-3-carboxy-phenyl, 3-fluoro-4-carboxy-phenyl, 3,5-difluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 4-(hydroxy-amino-carbonyl)-phenyl, 3-fluoro-4-(2-methoxy-ethyl-amino-carbonyl)-phenyl, 4-(cyclopropyl-amino-carbonyl)-phenyl, 3,5-difluoro-4-(amino-carbonyl)-phenyl, 4-(N-methyl, N-hydroxy-amino-carbonyl)-phenyl, 3-fluoro-4-(2-hydroxy-2-methyl-n-propyl-amino-carbonyl)-phenyl, 4-(N-hydroxy-amidino)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(1-methyl-imidazol-2-yl)-phenyl, 4-(2-methyl-oxazol-4-yl)-phenyl, 4-(1,2,4-oxadiazol-3-yl)-phenyl, 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl, 4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 2-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(2-methyl-1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-1-yl)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, 4-(1,2,4-triazol-3-yl)-phenyl, 4-(1-methyl-1,2,3-triazol-5-yl)-phenyl, 4-(1-methyl-1,2,4-triazol-3-yl)-phenyl, 4-(1,2,3,4-tetrazol-1-yl)-phenyl, 4-(1,2,3,4-tetrazol-5-yl)-phenyl, and 4-(1-methyl-1,2,3,4-tetrazol-5-yl)-phenyl, and 4-(4,5-dihydropyridazin-6-yl-3(2H)-one)-phenyl; (b) quinoxalin-6-yl, 2-(1R*-hydroxy-ethyl)-quinoxalin-6-yl, 2-(1S*-hydroxy-ethyl)-quinoxalin-6-yl, quinolin-6-yl, 4-hydroxy-quinolin-6-yl, 3-fluoro-quinolin-6-yl, 2-(ethoxy-ethoxy)-quinolin-6-yl, 2-amino-quinolin-6-yl, 2-(dimethyl-amino)-quinolin-6-yl, 4-(dimethyl-amino)-quinolin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, 3,4-dihydroquinolin-6-yl-2-one, quinazolin-7-yl-4-one, 6-methyl-quinazolin-6-yl-4-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy, N-methyl-amino-carbonyl)-indol-5-yl, 3,3-dimethyl-indolin-5-yl-2-one, indolin-5-yl-2-one, 3,3-difluoro-indolin-5-yl-2-one, 3-methyl-indolin-7-yl-2-one, 2-hydroxy-isoindolin-5-yl-1-one, 1-carboxy-2,3-dihydro-1H-inden-6-yl, 2H-indazol-5-yl, 3-hydroxy-1H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(2-methoxy-ethyl)-2H-indazol-5-yl, 1-(2-methoxy-ethyl)-1H-indazol-5-yl, 2-(difluoro-methyl)-2H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, benzimidazol-6-yl, benzoxazol-6-yl, benzothiazol-6-yl, 2-(2-hydroxy-n-prop-2-yl)-benzthiazol-5-yl, 2-(1R*-hydroxy-ethyl)-benzthiazol-5-yl, 2-(1S*-hydroxy-ethyl)-benzthiazol-5-yl, 3-amino-benzisoxazol-6-yl, 2H-benzo[d][1,2,3]triazol-5-yl, and 2-methyl-2H-benzo[d][1,2,3]triazol-5-yl, and (c) spiro[cyclopropane-1,3′-indolin-5-yl]-2′-one or spiro[cyclopentane-1,3′-indolin-5′-yl]-2-one; or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.
 6. The compound of claim 1, wherein R¹ is selected from the group consisting of difluoro-methoxy, 2,2,2-trifluoro-ethoxy, 4-(trifluoro-methyl)-1,2,3-triazol-1-yl, and 1,2,3,4-tetrazol-1-yl a is an integer from 1 to 2; each R² is independently selected from the group consisting of 2-fluoro and 3-chloro; R³ is hydrogen; R⁴ is hydrogen; Q is selected from the group consisting of 2-fluoro-3-carboxy-phenyl, 3-fluoro-4-carboxy-phenyl, 3,5-difluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 4-(hydroxy-amino-carbonyl)-phenyl, 3-fluoro-4-(2-methoxy-ethyl-amino-carbonyl)-phenyl, 4-(cyclopropyl-amino-carbonyl)-phenyl, 3,5-difluoro-4-(amino-carbonyl)-phenyl, 4-(N-methyl, N-hydroxy-amino-carbonyl)-phenyl, 3-fluoro-4-(2-hydroxy-2-methyl-n-propyl-amino-carbonyl)-phenyl, 4-(N-hydroxy-amidino)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(1-methyl-imidazol-2-yl)-phenyl, 4-(2-methyl-oxazol-4-yl)-phenyl, 4-(1,2,4-oxadiazol-3-yl)-phenyl, 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl, 4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 2-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(2-methyl-1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-1-yl)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, 4-(1,2,4-triazol-3-yl)-phenyl, 4-(1-methyl-1,2,3-triazol-5-yl)-phenyl, 4-(1-methyl-1,2,4-triazol-3-yl)-phenyl, 4-(1,2,3,4-tetrazol-1-yl)-phenyl, 4-(1,2,3,4-tetrazol-5-yl)-phenyl, and 4-(1-methyl-1,2,3,4-tetrazol-5-yl)-phenyl, and 4-(4,5-dihydropyridazin-6-yl-3(2H)-one)-phenyl; and wherein the Ring stereo-center is present as a racemate or in stereo-isomeric excess of the R*, S*, R or S stereo-isomer; or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.
 7. The compound of claim 1, wherein R¹ is selected from the group consisting of 4-chloro-1,2,3-triazol-1-yl, 4-(trifluoro-methyl)-1,2,3-triazol-1-yl, 1,2,3,4-tetrazol-1-yl, and 5-deutero-1,2,3,4-tetrazol-1-yl; a is 2; and the two R² are 2-fluoro and 3-chloro; R³ is selected from the group consisting of hydrogen ad methyl R⁴ is selected from the group consisting of hydrogen, methyl, S*-methyl, R*-methyl, S-methoxy and R-methoxy; Q is selected from the group consisting of quinoxalin-6-yl, 2-(1R*-hydroxy-ethyl)-quinoxalin-6-yl, 2-(1S*-hydroxy-ethyl)-quinoxalin-6-yl, quinolin-6-yl, 4-hydroxy-quinolin-6-yl, 3-fluoro-quinolin-6-yl, 2-(ethoxy-ethoxy)-quinolin-6-yl, 2-amino-quinolin-6-yl, 2-(dimethyl-amino)-quinolin-6-yl, 4-(dimethyl-amino)-quinolin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, 3,4-dihydroquinolin-6-yl-2-one, quinazolin-7-yl-4-one, 6-methyl-quinazolin-6-yl-4-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy,N-methyl-amino-carbonyl)-indol-5-yl, 3,3-dimethyl-indolin-5-yl-2-one, indolin-5-yl-2-one, 3,3-difluoro-indolin-5-yl-2-one, 3-methyl-indolin-7-yl-2-one, 2-hydroxy-isoindolin-5-yl-1-one, 1-carboxy-2,3-dihydro-1H-inden-6-yl, 2H-indazol-5-yl, 3-hydroxy-1H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(2-methoxy-ethyl)-2H-indazol-5-yl, 1-(2-methoxy-ethyl)-1H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(difluoro-methyl)-2H-indazol-5-yl, benzimidazol-6-yl, benzoxazol-6-yl, benzothiazol-6-yl, 2-(2-hydroxy-n-prop-2-yl)-benzthiazol-5-yl, 2-(1R*-hydroxy-ethyl)-benzthiazol-5-yl, 2-(1S*-hydroxy-ethyl)-benzthiazol-5-yl, 3-amino-benzisoxazol-6-yl, 2H-benzo[d][1,2,3]triazol-5-yl, 2-methyl-2H-benzo[d][1,2,3]triazol-5-yl, spiro[cyclopropane-1,3′-indolin-5-yl]-2′-one or spiro[cyclopentane-1,3′-indolin-5′-yl]-2-one; and wherein the Ring stereo-center is present as a racemate or in stereo-isomeric excess of the R*, S*, R or S stereo-isomer; or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.
 8. The compound of claim 1, wherein R¹ is selected from the group consisting of difluoromethoxy, 2,2,2-trifluoroethoxy, 4-(trifluoromethyl)-1,2,3-triazol-1-yl, 1,2,3,4-tetrazol-1-yl and 5-deutero-1,2,3,4-tetrazol-1-yl; a is an integer from 1 to 2; each R² is independently selected from the group consisting of 2-fluoro, and 3-chloro; R³ is selected from the group consisting of hydrogen and methyl; R⁴ is selected from the group consisting of hydrogen, methyl, S*-methyl, and R-methoxy; Q is selected from the group consisting of (a) 3-fluoro-4-carboxy-phenyl, 3,5-difluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 3-fluoro-4-(2-methoxy-ethyl-amino-carbonyl)-phenyl, 3,5-difluoro-4-(amino-carbonyl)-phenyl, 4-(N-methyl, N-hydroxy-amino-carbonyl)-phenyl, 4-(N-hydroxy-amidino)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(2-methyl-oxazol-4-yl)-phenyl, 4-(1,2,4-oxadiazol-3-yl)-phenyl, 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 2-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-1-yl)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, 4-(1,2,4-triazol-3-yl)-phenyl, 4-(1-methyl-1,2,4-triazol-3-yl)-phenyl, 4-(1,2,3,4-tetrazol-1-yl)-phenyl, and 4-(1,2,3,4-tetrazol-5-yl)-phenyl; (b) quinoxalin-6-yl, 2-(1R*-hydroxy-ethyl)-quinoxalin-6-yl, 2-(1S*-hydroxy-ethyl)-quinoxalin-6-yl, quinolin-6-yl, 4-hydroxy-quinolin-6-yl, 3-fluoro-quinolin-6-yl, 2-amino-quinolin-6-yl, 2-(dimethyl-amino)-quinolin-6-yl, 4-(dimethyl-amino)-quinolin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, 3,4-dihydroquinolin-6-yl-2-one, quinazolin-7-yl-4-one, 6-methyl-quinazolin-6-yl-4-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy,N-methyl-amino-carbonyl)-indol-5-yl, indolin-5-yl-2-one, 3,3-difluoro-indolin-5-yl-2-one, 2H-indazol-5-yl, 3-hydroxy-1H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(2-methoxy-ethyl)-2H-indazol-5-yl, 1-(2-methoxy-ethyl)-2H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(difluoro-methyl)-2H-indazol-5-yl, benzimidazol-6-yl, benzoxazol-6-yl, benzothiazol-6-yl, 2-(1S*-hydroxy-ethyl)-benzthiazol-5-yl, 3-amino-benzisoxazol-6-yl, 2H-benzo[d][1,2,3]triazol-5-yl, and 2-methyl-2H-benzo[d][1,2,3]triazol-5-yl, and (c) spiro[cyclopropane-1,3′-indolin-5-yl]-2′-one; and wherein the Ring stereo-center is present as a racemate or in stereo-isomeric excess of the R*, S*, R or S stereo-isomer; or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.
 9. The compound of claim 1, wherein R¹ is 1,2,3,4-tetrazol-1-yl; a is 2; and the two R² are 2-fluoro, and 3-chloro; R³ is selected from the group consisting of hydrogen and methyl; R⁴ is selected from the group consisting of hydrogen, methyl, S*-methyl, and R-methoxy; Q is selected from the group consisting of (a) 3-fluoro-4-carboxy-phenyl, 3,5-difluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 3-fluoro-4-(2-methoxy-ethyl-amino-carbonyl)-phenyl, 3,5-difluoro-4-(amino-carbonyl)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(1,2,4-oxadiazol-3-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 2-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-1-yl)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, 4-(1,2,4-triazol-3-yl)-phenyl, 4-(1-methyl-1,2,4-triazol-3-yl)-phenyl, and 4-(1,2,3,4-tetrazol-5-yl)-phenyl; (b) quinoxalin-6-yl, 2-(1R*-hydroxy-ethyl)-quinoxalin-6-yl, 2-(1S*-hydroxy-ethyl)-quinoxalin-6-yl, quinolin-6-yl, 4-hydroxy-quinolin-6-yl, 3-fluoro-quinolin-6-yl, 2-amino-quinolin-6-yl, 4-(dimethyl-amino)-quinolin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, 3,4-dihydroquinolin-6-yl-2-one, quinazolin-7-yl-4-one, 6-methyl-quinazolin-6-yl-4-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy,N-methyl-amino-carbonyl)-indol-5-yl, indolin-5-yl-2-one, 2H-indazol-5-yl, 3-hydroxy-1H-indazol-5-yl, 2-methyl-2H-indazol-5-yl, 2-(2-methoxy-ethyl)-2H-indazol-5-yl, 2-(difluoro-methyl)-2H-indazol-5-yl, benzimidazol-6-yl, benzoxazol-6-yl, benzothiazol-6-yl 3-amino-benzisoxazol-6-yl, and 2H-benzo[d][1,2,3]triazol-5-yl; and wherein the Ring stereo-center is present as a racemate or in stereo-isomeric excess of the R*, S*, R or S stereo-isomer; or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.
 10. The compound of claim 1, wherein R¹ is 1,2,3,4-tetrazol-1-yl; a is 2; and the two R² are 2-fluoro, and 3-chloro; R³ is hydrogen; R⁴ is selected from the group consisting of hydrogen, methyl, S*-methyl, and R-methoxy; Q is selected from the group consisting of (a) 3-fluoro-4-carboxy-phenyl, 3,5-difluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, 4-(1,2,4-triazol-3-yl)-phenyl, 4-(1-methyl-1,2,4-triazol-3-yl)-phenyl, and 4-(1,2,3,4-tetrazol-5-yl)-phenyl; (b) quinoxalin-6-yl, 2-(1R*-hydroxy-ethyl)-quinoxalin-6-yl, 2-(1S*-hydroxy-ethyl)-quinoxalin-6-yl, quinolin-6-yl, 4-hydroxy-quinolin-6-yl, 2-amino-quinolin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, quinazolin-7-yl-4-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy,N-methyl-amino-carbonyl)-indol-5-yl, 2-(2-methoxy-ethyl)-2H-indazol-5-yl, 2-(difluoro-methyl)-2H-indazol-5-yl, benzothiazol-6-yl, 3-amino-benzisoxazol-6-yl, and 2H-benzo[d][1,2,3]triazol-5-yl; and wherein the Ring stereo-center is present as a racemate or in stereo-isomeric excess of the R*, S*, R or S stereo-isomer; or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.
 11. The compound of claim 1, wherein R¹ is 1,2,3,4-tetrazol-1-yl; a is 2; and the two R² are 2-fluoro, and 3-chloro; R³ is hydrogen; R⁴ is selected from the group consisting of hydrogen, and S*-methyl; Q is selected from the group consisting of (a) 3-fluoro-4-carboxy-phenyl, 4-(2-carboxy-ethen-1-yl)-phenyl, 4-(imidazol-2-yl)-phenyl, 4-(1,3,4-oxadiazol-5-yl-2-one)-phenyl, 4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 3-fluoro-4-(1,2,4-oxadiazol-3-yl-5-one)-phenyl, 4-(1,2,3-triazol-5-yl)-phenyl, and 4-(1,2,3,4-tetrazol-5-yl)-phenyl; (b) quinoxalin-6-yl, 4-hydroxy-quinolin-6-yl-2-one, 2-carboxy-3-fluoro-indol-5-yl, 2-(N-hydroxy,N-methyl-amino-carbonyl)-indol-5-yl, and 2-(difluoro-methyl)-2H-indazol-5-yl; and wherein the Ring stereo-center is present as a racemate or in stereo-isomeric excess of the R*, S*, R or S stereo-isomer; or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.
 12. The compound of claim 1, selected from the group consisting of (3S*, 8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-N-(2′-oxospiro[cyclopentane-1,3′-indolin]-5′-yl)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide; (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-N-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide; (3S,8aS*)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide; (3S,8aR*)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-N-[3-fluoro-4-(5-oxo-2H-1,2,4-oxadiazol-3-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide; (3S,8aS*)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(3-fluoro-4-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxamide; (3S,8R*)-4-[[7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carbonyl]amino]-2-fluoro-benzoic acid; (3S,8aR*)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-N-[4-(5-oxo-2H-1,2,4-oxadiazol-3-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide; (3S,8aR*)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-N-[4-(1H-tetrazol-5-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide; (3 S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-N-[4-(1H-triazol-5-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indolizine-3-carboxamide; 5-[[(3 S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizine-3-carbonyl]amino]-3-fluoro-1H-indole-2-carboxylic acid; and pharmaceutically acceptable salts thereof.
 13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim
 1. 14. (canceled)
 15. (canceled)
 16. A method for the treatment of (a) a thromboembolic disorder; (b) an inflammatory disorder or a disorder; or (c) a disease or condition in which plasma kallikrein activity is implicated, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim
 1. 17. The method of claim 16, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, and venous cerebrovascular thromboembolic disorders.
 18. The method of claim 16, wherein the thromboembolic disorder is selected from the group consisting of unstable angina, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from prosthetic valves or other implants, indwelling catheters, stents, cardiopulmonary bypass, hemodialysis, or other procedures in which blood is exposed to an artificial surface that promotes thrombosis.
 19. The method of claim 16, wherein the thromboembolic disorder is selected from the group consisting of hereditary angioedema (HAE) and diabetic macular edema (DME).
 20. The method of claim 16, wherein the inflammatory disorder is selected from the group consisting of sepsis, acute respiratory distress syndrome, and systemic inflammatory response syndrome.
 21. The method of claim 16, wherein the disease or condition in which plasma kallikrein activity is implicated is selected from the group consisting of impaired visual acuity, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, and cardiopulmonary bypass surgery.
 22. (canceled)
 23. (canceled)
 24. (canceled)
 25. (canceled)
 26. (canceled)
 27. (canceled)
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